Novel intermediates useful for the preparation of antihistaminic piperidine derivatives

ABSTRACT

The present invention is related to a novel intermediates and processes which are useful in the preparation of certain antihistaminic piperidine derivatives of the formula  
                 
 
     wherein  
     W represents —C(═O)— or —CH(OH)—;  
     R 1  represents hydrogen or hydroxy;  
     R 2  represents hydrogen;  
     R 1  and R 2  taken together form a second bond between the carbon atoms bearing R 1  and R 2 ;  
     n is an integer of from 1 to 5;  
     m is an integer 0 or 1;  
     R 3  is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched each of A is hydrogen or hydroxy; and  
     pharmaceutically acceptable salts and individual optical isomers thereof,  
     with the proviso that where R 1  and R 2  are taken together to form a second bond between the carbon atoms bearing R 1  and R 2  or where R 1  represented hydroxy, m is an integer 0.

BACKGROUND OF THE INVENTION

[0001] This is a Continuation-In-Part Application of patent applicationSer. No. 08/237,466, filed May 11, 1994 which is a Continuation-In-PartApplication of patent application Ser. No.08/144,084, filed Oct. 27,1993 which is a Continuation-In-Part Application of patent applicationSer. No. 08/082,693, filed Jun. 25, 1993.

[0002] The present invention is related to novel intermediates which areuseful in the preparation of certain piperidine derivatives which areuseful as antihistamines, antiallergy agents and bronchodilators [U.S.Pat. No. 4,254,129, Mar. 3, 1981, U.S. Pat. No. 4,254,130, Mar. 3, 1981,U.S. Pat. No. 4,285,958, Apr. 25, 1981 and U.S. Pat. No. 4,550,116, Oct.29, 1985].

[0003] These antihistaminic piperidine derivatives can be described bythe following formula:

[0004] wherein

[0005] W represents —C(═O)— or —CH(OH)—;

[0006] R₁ represents hydrogen or hydroxy;

[0007] R₂ represents hydrogen;

[0008] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0009] n is an integer of from 1 to 5;

[0010] m is an integer 0 or 1;

[0011] R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched;

[0012] each of A is hydrogen or hydroxy; and

[0013] pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0.

SUMMARY OF THE INVENTION

[0014] The present invention provides novel intermediates useful for thepreparation of certain antihistaminic piperidine derivatives of formula(I)

[0015] wherein

[0016] W represents —C(═O)— or —CH(OH)—;

[0017] R₁ represents hydrogen or hydroxy;

[0018] R₂ represents hydrogen; or

[0019] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0020] n is an integer of from 1 to 5;

[0021] m is an integer 0 or 1;

[0022] R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched;

[0023] each of A is hydrogen or hydroxy; and

[0024] pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0.

[0025] These novel intermediates are described by the followingformulas:

[0026] wherein

[0027] A is a hydrogen or hydroxy; and

[0028] R₅ is H, —CH₂OD wherein D is hydrogen, acetate or benzoate, —CHO,Br, Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein the alkyl moiety hasfrom 1 to 6 carbon atoms and is straight or branched and R₆ and R₇ areeach independently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ takentogether with the nitrogen atom form a pyrrolidine, piperidine ormorpholine, with the proviso that R₆ and R₇ cannot both be representedby C₁-C₆alkoxy.

[0029] wherein

[0030] A is a hydrogen or hydroxy; and

[0031] R₅ is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein thealkyl moiety has from 1 to 6 carbon atoms and is straight or branchedand R₆ and R₇ are each independently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆and R₇ taken together with the nitrogen atom form a pyrrolidine,piperidine or morpholine, with the proviso that R₆ and R₇ cannot both berepresented by C₁-C₆alkoxy.

[0032] wherein

[0033] A is a hydrogen or hydroxy; and

[0034] R₅ is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein thealkyl moiety has from 1 to 6 carbon atoms and is straight or branchedand R₆ and R₇ are each independently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆and R₇ taken together with the nitrogen atom form a pyrrolidine,piperidine or morpholine, with the proviso that R₆ and R₇ cannot both berepresented by C₁-C₆alkoxy.

[0035] wherein

[0036] Hal is Cl, Br or I;

[0037] n is an integer of from 1 to 5;

[0038] A is a hydrogen or hydroxy; and

[0039] R₅ is H, CH₂OD wherein D is hydrogen, acetate or benzoate, CHO,Br, Cl, I, CN, —COOH or —CONR₆R₇ wherein R₆ and R₇ are eachindependently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken togetherwith the nitrogen atom form a pyrrolidine, piperidine or morpholine,with the proviso that R₆ and R₇ cannot both be represented byC₁-C₆alkoxy.

[0040] wherein

[0041] Hal is Cl, Br or I;

[0042] n is an integer of from 1 to 5;

[0043] A is a hydrogen or hydroxy; and

[0044] R₅ is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein thealkyl moiety has from 1 to 6 carbonatoms and is straight or branched andR₆ and R₇ are each independently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇taken together with the nitrogen atom form a pyrrolidine, piperidine ormorpholine, with the proviso that R₆ and R₇ cannot both be representedby C₁-C₆alkoxy.

[0045] wherein

[0046] Hal is Cl, Br or I;

[0047] n is an integer of from 1 to 5;

[0048] A is a hydrogen or hydroxy;

[0049] R₅ is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein thealkyl moiety has from 1 to 6 carbon atoms and is straight or branchedand R₆ and R₇ are each independently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆and R₇ taken together with the nitrogen atom form a pyrrolidine,piperidine or morpholine, with the proviso that R₆ and R₇ cannot both berepresented by C₁-C₆alkoxy.

[0050] wherein

[0051] Hal is Cl, Br or I;

[0052] n is an integer of from 1 to 5; and

[0053] A is a hydrogen or hydroxy.

[0054] wherein

[0055] A is a hydrogen or hydroxy.

[0056] wherein

[0057] Hal is Cl, Br or I;

[0058] n is an integer of from 1 to 5;

[0059] A is a hydrogen or hydroxy; and

[0060] R₅ is H, CH₂OD wherein D is hydrogen, acetate or benzoate, CHO,Br, Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ wherein the alkyl moiety hasfrom 1 to 6 carbon atoms and is straight or branched and R₆ and R₇ areeach independently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ takentogether with the nitrogen atom form a pyrrolidine, piperidine ormorpholine, with the proviso that R₆ and R₇ cannot both be representedby C₁-C₆alkoxy; and

[0061] individual optical isomers thereof.

[0062] wherein

[0063] W represents —C(═O)— or —CH(OH)—;

[0064] R₁ represents hydrogen or hydroxy;

[0065] R₂ represents hydrogen; or

[0066] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0067] n is an integer of from 1 to 5;

[0068] m is an integer 0 or 1;

[0069] R₅ is H, Br, Cl, I, CN or —CONR₆R₇ wherein R₆ and R₇ are eachindependently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken togetherwith the nitrogen atom form a pyrrolidine, piperidine or morpholine,with the proviso that R₆ and R₇ cannot both be represented byC₁-C₆alkoxy;

[0070] A is hydrogen or hydroxy; and

[0071] pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0.

[0072] In addition, the present invention provides novel processes forpreparing the antihistaminic piperidine derivatives of formula

[0073] wherein

[0074] W represents —C(═O)— or —CH(OH)—;

[0075] R₁ represents hydrogen or hydroxy;

[0076] R₂ represents hydrogen; or

[0077] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0078] n is an integer of from 1 to 5;

[0079] m is an integer 0 or 1;

[0080] R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched;

[0081] each of A is hydrogen or hydroxy; and

[0082] pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

[0083] (a) reacting a cumene compound of the formula

[0084] wherein A is as defined above with a ω-halo compound of theformula

[0085] wherein B is halo or hydroxy, Hal represents Cl, Br or I and n isas defined above, in the presence of a suitable Lewis acid to produce aω-halo cumylketone compound;

[0086] (b) reacting the ω-halo cumylketone compound with a suitablehalogenating agent to give a ω-halo-halocumylketone compound;

[0087] (c) reacting the ω-halo-halocumylketone compound compound with asuitable cyanating agent to give a ω-halo-cyanocumylketone compound;

[0088] (d) reacting the ω-halo-cyanocumylketone compound with anappropriate straight or branched C₁-C₆ alcohol in the presence of asuitable anhydrous acid to give aω′-halo-α′-keto-α,α-dimethylphenylacetic acid imidate compound;

[0089] (e) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acidimidate compound with water to give aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound;

[0090] (f) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound with a piperidine compound of the formula

[0091] wherein R₁, R₂ and m are as defined above in the presence of asuitable non-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)—;

[0092] (g) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)— to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—;

[0093] (h) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)— or theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or theω-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—; and

[0094] (i) optionally reacting theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R₃ is—COOalkyl and W is —C(═O)—; and

[0095] (j) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent,

[0096] with the proviso that each of the hydroxy groups present in thecompounds described in steps a-i are optionally protected orunprotected.

[0097] In addition, the present invention provides novel processes forpreparing the antihistaminic piperidine derivatives of formula

[0098] wherein

[0099] W represents —C(═O)— or —CH(OH)—;

[0100] R₁ represents hydrogen or hydroxy;

[0101] R₂ represents hydrogen; or

[0102] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0103] n is an integer of from 1 to 5;

[0104] m is an integer 0 or 1;

[0105] R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched;

[0106] each of A is hydrogen or hydroxy; and

[0107] pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

[0108] (a) reacting a ω-halo-halocumylketone compound with carbondioxide under electrochemical reduction conditions to give aω′-halo-α′-keto-α,α-dimethylphenylacetic compound;

[0109] (b) reacting the ω′-halo-α′-keto-α,α-dimethylphenylaceticcompound compound with an appropriate straight or branched C₁-C₆ alcoholin the presence of a suitable anhydrous acid to give aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound;

[0110] (c) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound with a piperidine compound of the formula wherein R₁, R₂and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W═—C(═O)—;

[0111] (d) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is

[0112] COOalkyl and W is —C(═O)— to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—;

[0113] (e) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)— or theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—; and

[0114] (f) optionally reacting theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and

[0115] (g) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent,

[0116] with the proviso that each of the hydroxy groups present in thecompounds described in steps a-f are optionally protected orunprotected.

[0117] In addition, the present invention provides novel processes forpreparing the antihistaminic piperidine derivatives of formula

[0118] wherein

[0119] W represents —C(═O)— or —CH(OH)—;

[0120] R₁ represents hydrogen or hydroxy;

[0121] R₂ represents hydrogen; or

[0122] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0123] n is an integer 3;

[0124] m is an integer 0 or 1;

[0125] R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched;

[0126] each of A is hydrogen or hydroxy; and

[0127] pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

[0128] (a) reacting a cumyl compound of the formula

[0129] wherein A is as defined above with an appropriate cyclopropylcompound of the structure

[0130] wherein B is halo or hydroxy, in the presence of a suitable Lewisacid to produce a cyclopropyl cumylketone compound;

[0131] (b) reacting the cyclopropyl cumylketone compound with a suitablehalogenating agent to give a cyclopropyl halocumylketone compound;

[0132] (c) reacting the cyclopropyl halocumylketone compound with carbondioxide under electrochemical reduction conditions to give acyclopropylketo-α,α-dimethylphenylacetic acid compound;

[0133] (d) reacting the cyclopropylketo-α,α-dimethylphenylacetic with anappropriate straight or branched C₁-C₆ alcohol in the presence of asuitable anhydrous acid to give aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound;

[0134] (e) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound with a piperidine compound of the formula

[0135] wherein R₁, R₂ and m are as defined above in the presence of asuitable non-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W═—C(═O)—;

[0136] (f) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)— to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—;

[0137] (g) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)— or theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—; and

[0138] (h) optionally reacting theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and

[0139] (i) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent,

[0140] with the proviso that each of the hydroxy groups present in thecompounds described in steps a-h are optionally protected orunprotected.

[0141] Another embodiment of the present invention involves a processfor preparing the piperidine derivatives of formula

[0142] wherein

[0143] W represents —C(═O)— or —CH(OH)—;

[0144] R₁ represents hydrogen or hydroxy;

[0145] R₂ represents hydrogen; or

[0146] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0147] n is an integer of from 1 to 5;

[0148] m is an integer 0 or 1;

[0149] R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched;

[0150] each of A is hydrogen or hydroxy; and

[0151] pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

[0152] (a) reacting a α,α-dimethylphenylacetic acid amide compound ofthe formula

[0153] wherein A is as defined above and R₆ and R₇ are eachindependently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken togetherwith the nitrogen atom for a pyrrolidine, piperidine or morpholine, withthe proviso that R₆ and R₇ cannot both be represented by C₁-C₆alkoxywith a ω-halo compound of the formula

[0154] wherein B is halo or hydroxy, Hal represents Cl, Br or I and n isas defined above, in the presence of a suitable Lewis acid to produce aω′-halo-α′-keto-α,α-dimethylphenylacetic acid amide compound;

[0155] (b) reacting the ω′-halo-a-keto-a,-dimethylphenylacetic acidamide compound with a piperidine compound of the formula

[0156] wherein R₁ and R₂ are as defined above in the presence of asuitable non-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (XI)wherein R₅ is —CONR₆R7 wherein R6 and R₇ are as defined above;

[0157] (c) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (XI)wherein R₅ is —CONR₆R₇ wherein R₆ and R₇ are as defined above to producea ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—;

[0158] (d) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)—; and

[0159] (e) optionally reacting theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)-with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and

[0160] (f) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent,

[0161] with the proviso that each of the hydroxy groups present in thecompounds described in steps a-e are optionally protected orunprotected.

[0162] Another embodiment of the present invention involves a processfor preparing the piperidine derivatives of formula

[0163] wherein

[0164] W represents —C(═O)— or —CH(OH)—;

[0165] R₁ represents hydrogen or hydroxy;

[0166] R₂ represents hydrogen; or

[0167] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0168] n is an integer of from 1 to 5;

[0169] m is an integer 0 or 1;

[0170] R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched;

[0171] each of A is hydrogen or hydroxy; and

[0172] pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

[0173] (a) reacting a toluene compound of the formula

[0174] wherein A is as defined above with a ω-halo compound of theformula

[0175] wherein B is halo or hydroxy, Hal represents Cl, Br or I and n isas defined above, in the presence of a suitable Lewis acid to produce aω-halo-tolylketone compound;

[0176] (b) reacting the ω-halo-tolylketone compound with a suitable baseto give a cyclopropyl-tolylketone compound;

[0177] (c) reacting the cyclopropyl-tolylketone compound with a suitablehalogenating agent to give a cyclopropyl-halotolylketone compound;

[0178] (d) reacting the cyclopropyl-halotolylketone compound with asuitable cyanating agent to give a cyclopropyl cyanotolylketonecompound;

[0179] (e) reacting the cyclopropyl cyanotolylketone compound with asuitable methylating agent to give a cyclopropyl cyanocumylketonecompound;

[0180] (f) reacting the cyclopropyl cyanocumylketone compound with asuitable base to give a cyclopropylketo-α,α-dimethylphenylacetic acidamide;

[0181] (g) reacting the cyclopropylketo-α,α-dimethylphenylacetic acidamide with an appropriate straight or branched C₁-C₆ alcohol in thepresence of a suitable anhydrous acid to give aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound;

[0182] (h) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound with a piperidine compound of the formula

[0183] wherein R₁, R₂ and m are as defined above in the presence of asuitable non-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative;.

[0184] (i) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—;

[0185] (j) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative ofFormula (I) wherein R₃ is —COOH and W is —CH(OH)—; and

[0186] (k) optionally reacting theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— orω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (II)wherein R₃ is —COOalkyl and W is —C(═O)—; and

[0187] (l) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (II)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (II)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-a,-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is—COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,

[0188] with the proviso that each of the hydroxy groups present in thecompounds described in steps a-k are optionally protected orunprotected.

[0189] Another embodiment of the present invention involves a processfor preparing the piperidine derivatives of formula

[0190] wherein

[0191] W represents —C(═O)— or —CH(OH)—;

[0192] R₁ represents hydrogen or hydroxy;

[0193] R₂ represents hydrogen; or

[0194] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0195] n is an integer of from 1 to 5;

[0196] m is an integer 0 or 1;

[0197] R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched;

[0198] each of A is hydrogen or hydroxy; and

[0199] pharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer 0, comprising the steps of:

[0200] (a) reacting a phenylacetic acid ester compound of the formula

[0201] wherein A is as defined above with a ω-halo compound of theformula

[0202] wherein B is halo or hydroxy, Hal represents Cl, Br or I and n isas defined above, in the presence of a suitable Lewis acid to produce aω′-halo-α′-keto-phenylacetic acid ester compound;

[0203] (b) reacting the ω′-halo-α′-keto-phenylacetic acid ester compoundwith a suitable methylating agent in the presence of a suitable base togive a cyclopropylketo-α,α-dimethylphenylacetic acid ester;

[0204] (c) purifying the cyclopropylketo-α,α-dimethylphenylacetic acidester by distillation and/or recrystallization;

[0205] (d) reacting the cyclopropylketo-α,α-dimethylphenylacetic acidester with an appropriate straight or branched C₁-C₆ alcohol in thepresence of a suitable anhydrous acid to give aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound;

[0206] (e) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound with a piperidine compound of the formula

[0207] wherein R₁, R₂ and m are as defined above in the presence of asuitable non-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—;

[0208] (f) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)— to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—;

[0209] (g) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)—; and

[0210] (h) optionally reacting theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and

[0211] (i) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is—COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,

[0212] with the proviso that each of the hydroxy groups present in thecompounds described in steps a-h are optionally protected orunprotected.

[0213] (g) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)—; and

[0214] (h) optionally reacting theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and (i) optionally reactingthe ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is—COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,

[0215] with the proviso that each of the hydroxy groups present in thecompounds described in steps a-h are optionally protected orunprotected.

[0216] As used herein, the term “C₁-C₆alkyl” or “alkyl” refers to astraight or branched alkyl group having from 1 to 6 carbon atoms and asreferred to herein are methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl. The term“C₁-C₆alkoxy” refers to a straight or branched alkoxy group having from1 to 6 carbon atoms and as referred to herein are methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy,neopentoxy and n-hexoxy. The term “Hal” or “halo” refers to a halogengroup and includes Cl, Br or I.

[0217] The piperidine derivatives of the formula (IX) can formpharmaceutically acceptable salts. Pharmaceutically acceptable acidaddition salts of the compounds of this invention are those of anysuitable inorganic or organic acid. Suitable inorganic acids are, forexample, hydrochloric, hydrobromic, sulfuric, and phosphoric acids.Suitable organic acids include carboxylic acids, such as, acetic,propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic,tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, anddihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic,4-hydroxybenzoic, anthranillic, cinnamic, salicyclic, 4-aminosalicyclic,2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid, sulfonic acids,such as, methanesulfonic, ethanesulfonic and β-hydroxyethanesulfonicacid. Non-toxic salts of the compounds of the above-identified formulaformed with inorganic or organic bases are also included within thescope of this invention and include, for example, those of alkalimetals, such as, sodium, potassium and lithium, alkaline earth metals,for example, calcium and magnesium, light metals of group IIIA, forexample, aluminum, organic amines, such as, primary, secondary ortertiary amines, for example, cyclohexylamine, ethylamine, pyridine,methylaminoethanol and piperazine. The salts are prepared byconventional means as, for example, by treating a piperidine derivativeof formula (I) with an appropriate acid or base.

[0218] The novel intermediates of formula (II), formula (III), formula(IV), formula (V), formula (VI) and formula (VII) wherein R₅ is hydrogenmay be prepared as described in Scheme A. In Scheme A, all substituentsare as previously defined unless otherwise indicated.

[0219] Scheme A provides various general synthetic procedures forpreparing the novel intermediates of formula (II), formula (III) andformula (IV) wherein R₅ is hydrogen.

[0220] In step a, the appropriate toluene derivative of structure (1) ismethylated to give the corresponding ethylbenzene derivative ofstructure (2).

[0221] For example, the appropriate toluene derivative of structure (1)is reacted with a slight molar excess of an appropriate methylatingagent, such as iodomethane, chloromethane or bromomethane in thepresence of a suitable non-nucleophilic base, such as potassiumt-butoxide or sodium hydride. The reaction is typically conducted in asuitable organic solvent, such as diglyme, tert-butyl methyl ether ormethylene chloride, for a period of time ranging from 30 minutes to 24hours and at a temperature range of from −78° C. to room temperature.The corresponding ethylbenzene derivative of structure (2) is recoveredfrom the reaction zone by extractive methods as is known in the art andmay be purified by distillation.

[0222] In step b, the appropriate ethylbenzene derivative of structure(2) is methylated to give the corresponding cumene derivative ofstructure (3) as described previously in step a, but using at least 2molar equivalents of methylating agent.

[0223] In step c, the appropriate toluene derivative of structure (1) isdimethylated to give the corresponding cumeme derivative of structure(3) as described previously in step a but using at least 2 molarequivalents of methylating agent.

[0224] In step d, the appropriate toluene derivative of structure (1) isacylated with an appropriate ω-halo compound of the structureHal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the corresponding ω-halotolylketone compound of structure (4).

[0225] For example, the appropriate ω-halo tolylketone compound ofstructure (4) may be prepared by reacting an appropriate toluenederivative of structure (1) with an appropriate ω-halo compound of thestructure Hal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl,Br or I and n is as previously defined, which are known in the art orare prepared by procedures well known in the art, under the generalconditions of a Friedel-Crafts acylation using a suitable Lewis acid.The reaction is carried out in a solvent, such as carbon disulfide,1,2-dichloroethane, n-hexane, acetonitrile, 1-nitropropane,nitromethane, diethyl ether and carbon tetrachloride, methylenechloride, tetrachloroethane or nitrobenzene with methylene chloridebeing the preferred solvent. The reaction time varies from about ½ hourto 25 hours, preferably 10 to 16 hours and the reaction temperaturevaries from about 0° C. to 25° C. The corresponding ω-halo tolylketonecompound of structure (4) is recovered from the reaction zone by anaqueous quench followed by extraction as is known in the art. The ω-halotolylketone compound of structure (4) may be purified by procedures wellknown in the art, such as crystallization and/or distillation.

[0226] Alternatively, the appropriate toluene derivative of structure(1) may be acylated with the ω-halo compound of the structureHal—(CH₂)_(n)—C(═O)—B, wherein B is hydroxy, Hal is Cl, Br or I and n isas previously defined in the presence of a Lewis acid to give thecorresponding ω-halo tolylketone compound of structure (4) as describedin Arch. Pharm. 306, 807 1973. In general, an appropriate toluenederivative of structure (1) and the ω-halo compound of the structureHal—(CH₂)_(n)—C(═O)—B, wherein B is hydroxy, are melted together atabout 50° C., then cooled to about 10° C. after which a Lewis acid isadded in an amount about 2.2 times the molar amount of the appropriatetoluene derivative of structure (1) employed. The mixture is heated atabout 70° C. for about 2 hours after which a 30% sodium acetate solutionis added and extracted with ether. The organic layer is dried and thesolvent evaporated to give the corresponding ω-halo tolylketone compoundof structure (4). The ω-halo tolylketone compound of structure (4) maybe purified by procedures well known in the art, such as crystallizationand/or distillation.

[0227] Suitable Lewis acids for the acylation reaction described in stepd are well known and appreciated in the art. Examples of suitable Lewisacids are boron trichloride, aluminum chloride, titanium tetrachloride,boron trifluoride, tin tetrachloride, ferric chloride, cobalt(II)chloride and zinc chloride, with aluminum chloride being preferred. Theselection and utilization of suitable Lewis acids for the acylationreaction of step d is well known and appreciated by one of ordinaryskill in the art.

[0228] The starting ω-halo compound of the structureHal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined are commercially available of easilyprepared by generally known methods.

[0229] While also not necessary for utilization in the acylationreaction of step d, the phenol functionality of those toluenederivatives of structure (1), wherein A is hydroxy may be protected witha suitable protecting group. For example, suitable protecting groups forthe phenolic hydroxy include methyl ether, 2-methoxyethoxymethyl ether(MEM), cyclohexyl ether, o-nitrobenzyl ether, 9-anthryl ether,t-butyldimethylsilyl ether, acetate, benzoate, methyl carbamate, benzylcarbamate, aryl pivaloate and aryl methanesulfonate.

[0230] In step e, to appropriate toluene derivative of structure (1) isacylated with an appropriate cyclopropyl compound of the structure

[0231] wherein B is as previously defined to give the correspondingcyclopropyl tolylketone derivative of structure (5) as describedpreviously in step d.

[0232] In step f, the appropriate ethylbenzene derivative of structure(2) is acylated with an appropriate ω-halo compound of the structureHal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the corresponding ω-haloethylphenylketone compound of structure (6) as described previously instep d.

[0233] In step g, the appropriate ethylbenzene derivative of structure(2) is acylated with an appropriate cyclopropyl compound of thestructure

[0234] wherein B is as previously defined to give the correspondingcyclopropyl ethylphenylketone derivative of structure (7) as describedpreviously in step e.

[0235] In step h, the appropriate cumene derivative of structure (3) isacylated with an appropriate ω-halo compound of the structureHal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the corresponding ω-halocumylketone compound of structure (8) as described previously in step d.

[0236] In step i, to appropriate cumene derivative of structure (3) isacylated with an appropriate cyclopropyl compound of the structure

[0237] wherein B is as previously defined to give the correspondingcyclopropyl cumylketone derivative of structure (9) as describedpreviously in step e.

[0238] In step j, the cyclopropyl functionality of the appropriatecyclopropyl tolylketone derivative of structure (5) is ring-opened togive the corresponding ω-halo tolylketone compound of structure (4)wherein n=3.

[0239] For example, the appropriate cyclopropyl tolylketone derivativeof structure (5) is reacted with an appropriate hydrogen halide in asuitable organic solvent, such as toluene, xylene and ethanol. Thereaction is typically conducted at a temperature range of from roomtemperature to 70° C. and for a period of time ranging from 20 minutesto 10 hours. The corresponding ω-halo tolylketone compound of structure(4) wherein n=3 is isolated from the reaction zone by evaporation of thesolvent or may be stored in a solution of the hydrogen halide.

[0240] In step k, the appropriate ω-halo tolylketone compound ofstructure (4) wherein n=3 is ring-closed to give the correspondingcyclopropyl tolylketone derivative of structure (5).

[0241] For example, the appropriate ω-halo tolylketone compound ofstructure (4) wherein n=3 is -reacted with an appropriatenon-nucleophilic base, such as sodium hydroxide or potassium hydroxidein a suitable organic protic solvent, such as methanol or ethanol. Thereaction is typically conducted at a temperature range of from −10° C.to room temperature and for a period of time ranging from 10 minutes to5 hours. The corresponding cyclopropyl tolylketone derivative ofstructure (5) is isolated from the reaction zone by extractive methodsas are known in the art and may be purified by distillation.

[0242] In step 1, the cyclopropyl functionality of the appropriatecyclopropyl ethylphenylketone derivative of structure (7) is ring-openedto give the corresponding ω-halo ethylphenylketone compound of structure(6) wherein n=3 as described previously in step j.

[0243] In step m, the appropriate ω-halo ethylphenylketone compound ofstructure (6) wherein n=3 is ring-closed to give the correspondingcyclopropyl ethylphenylketone derivative of structure (7) as describedpreviously in step k.

[0244] In step n, the cyclopropyl functionality of the appropriatecyclopropyl cumylketone derivative of structure (9) is ring-opened togive the corresponding ω-halo cumylketone compound of structure (8)wherein n=3 as described previously in step j.

[0245] In step o, the appropriate ω-halo cumylketone compound ofstructure (8) wherein n=3 is ring-closed to give the correspondingcyclopropyl cumylketone derivative of structure (9) as describedpreviously in step k.

[0246] In step p, the appropriate ω-halo ethylphenylketone compound ofstructure (6) is methylated to give the corresponding ω-halo cumylketonecompound of structure (8) as described previously in step a.

[0247] In step q, the appropriate cyclopropyl tolylketone derivative ofstructure (5) is dimethylated to give the corresponding cyclopropylcumylketone derivative of structure (9) as described previously in stepc.

[0248] In step r, the appropriate ω-halo tolylketone compound ofstructure (4) is methylated to give the corresponding ω-haloethylphenylketone compound of structure (6) as described previously instep a.

[0249] In step s, the appropriate ω-halo tolylketone compound ofstructure (4) is dimethylated to give the corresponding ω-halocumylketone compound of structure (8) as described previously in step c.

[0250] In step t, the appropriate cyclopropyl ethylphenylketonederivative of structure (7) is methylated to give the correspondingcyclopropyl cumylketone derivative of structure (9) as describedpreviously in step a.

[0251] In step u, the appropriate cyclopropyl tolylketone derivative ofstructure (5) is methylated to give the corresponding cyclopropylethylphenylketone derivative of structure (7) as described previously instep a.

[0252] Starting materials for use in Scheme A are readily available toone of ordinary skill in the art.

[0253] The following examples present typical syntheses as described inScheme A. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 1 Step h: 4-Chloro-1-(4-isopropyl-phenyl)-butan-1-one

[0254] Slurry aluminum chloride (140.9 g, 1.075 mol) and 4-chlorobutyrylchloride (148 g, 1.05 mol) in methylene chloride (1.0 L) add, bydropwise addition, cumene (125 g, 1.04 mol) over a thirty minute periodunder a nitrogen atmosphere while maintaining the internal temperaturebetween 5-8° C. with an ice bath. Allow the stirred solution to come toroom temperature and continue stirring under nitrogen for 14 hours.Cautiously add the methylene chloride solution to 1 L of crushed icewith stirring and add additional methylene chloride (400 mL). Separatethe organic phase and wash with 10% hydrochloric acid (3×300 mL), water(3×300 mL), 10% sodium bicarbonate (3×300 mL) and water (3×300 mL). Dry(MgSO₄), filter and wash with methylene chloride (150 mL). Evaporate thesolvent to give the title compound (203 g, 86%) as a clear oil whichcrystallizes on standing; mp 35-37° C.

[0255]¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J=8.2Hz, 2H), 7.31 (d, J=8.2Hz, 2H), 3.65 (t, J=6.3 Hz, 2H), 3.13 (t, J=6.9 Hz, 2H), 2.95 (p, J=6.9Hz, 1H), 2.20 (p, J=6.6 Hz, 2H), 1.26 (d, J=6.9 Hz, 6H); 13C NMR (75MHz, CDCl₃) δ 198.2, 154.4, 134.4, 128.1, 126.5, 44.5, 32.96, 34.0,26.7, 23.5; IR (CDCl₃) 2950, 2920, 1675, 1680, 1600, 1410, 1225 cm⁻¹; MS(GCCIMS (methane)) 255 (3), 251 (10), 227 (30 (M+H)), 225 (100 (M+H)),189 (70), 147 (95), 107 (13, 105 (40).

[0256] Anal. Calcd for C₁₃H₁₇OCl: C, 69.48; H, 7.62; Found: C, 69.31; H,7.39.

EXAMPLE 2 Step d: 4-Chloro-1-(4-methyl-phenyl)-butan-1-one

[0257] Suspend anhydrous AlCl3 (156 g, 1.15 mol) in toluene (1500 mL)and cool to 2-4° C. Add, by slow addition, a solution of 4-chlorobutyrylchloride (165.5 g, 1.15 mol) in toluene (300 mL). Stir for 15 minutesand pour into stirring ice-water (2.5 L). Stir for 30 hours, decant thetoluene and extract the aqueous phase with toluene (700 mL). Combine theorganic layers and wash three times with water (1 L, 1 L, 500 mL).Evaporate the solvent in vacuo to give the title compound as a paleyellow oil (292.3 g, 95%).

EXAMPLE 3 Step k: Cyclopropyl-p-tolyl-methanone

[0258] Dissolve potassium hydroxide (126 g) in methanol (450 mL), stirand cool in an ice-water bath. Add, by dropwise addition, a solution of4-chloro-1-(4-methyl-phenyl)-butan-1-one (292 g) in methanol (450 mL).Stir for 20 minutes at 8-10° C. and partially evaporate the methanol invacuo to give 400 mL of a residue. Pour the residue, with stirring, intowater (1500 mL), filter the white solid and dry under vacuum to give thetitle compound as a white solid (190.8 g, 90% ) .

[0259] The following compounds can be prepared using the methodologydepicted in Scheme A:

[0260] Cyclopropyl-(4-isopropyl-phenyl)-methanone;

[0261] Cyclopropyl-(4-ethyl-phenyl)-methanone; and

[0262] 4-Chloro-1-(4-ethyl-phenyl)-butan-1-one.

[0263] The novel intermediates of formula (II), formula (III), formula(IV), formula (V), formula (VI) and formula (VII) wherein R₅ is OH, Cl,Br or I may be prepared as described in Scheme B. In Scheme B, allsubstituents are as previously defined unless otherwise indicated.

[0264] Hal═Cl, Br or I

[0265] Scheme B provides various general synthetic procedures forpreparing the novel intermediates of formula (II), formula (III),formula (IV), formula (V), formula (VI) and formula (VII) wherein R₅ isOH, Cl, Br or I.

[0266] In step a, the appropriate ω-halo cumylketone compound ofstructure (8) is halogenated to give the correspondingω-halo-halocumylketone compound of structure (10).

[0267] For example, the appropriate ω-halo-halocumylketone compound ofstructure (10) may be prepared by reacting an appropriate ω-halocumylketone compound of structure (8) with a suitable halogenating agentoptionally in the presence of a catalytic amount of a suitableinitiator. Examples of suitable brominating agents areN-bromosuccinimide, and 1,3-dibromo-5,5-dimethyl hydantoin, withN-bromosuccinimide being preferred. An example of suitable chlorinatingagent is N-chlorosuccinimide and an example of a suitable iodinatingagent is N-iodosuccinimide. Examples of suitable initiators are benzoylperoxide, AIBN, t-butyl peroxide and ultraviolet light. The reaction iscarried out in a solvent, such as carbon tetrachloride, methylenechloride, 1,2-dichlorobenzene, 1,2-dichloroethane, ethyl formate orethyl acetate, with carbon tetrachloride being the preferred solvent.The reaction time varies from about ½ hour to 8 hours, preferably ½ to 2hours and the reaction temperature varies from about 25° C. to thereflux temperature of the solvent employed, preferably 70° C. to 80° C.The corresponding ω-halo-halocumylketone compound of structure (10) isrecovered from the reaction zone by extractive methods as are known inthe art followed by evaporation of the solvent.

[0268] In addition, the halogenation reaction of step a may be carriedout in a 2-phase procedure. For example, the appropriateω-halo-halocumylketone compound of structure (10) may be prepared byreacting an appropriate ω-halo cumylketone compound of structure (8)with a suitable halogenating agent, such as sodium bromate/sodiumbromide, in a solvent mixture such as methylene chloride and water,catalyzing the reaction with, for example, ultraviolet light. Thecorresponding ω-halo-halocumylketone compound of structure (10) isrecovered from the reaction zone by extractive methods as are known inthe art followed by evaporation of the solvent.

[0269] The ω-halo-halocumylketone compound of structure (10) maydehydrohalogenate to the corresponding α-methylstyrene, giving variousmixtures of ω-halo-halocumylketone compound of structure (10) andα-methylstyrene compounds. The α-methylstyrene compounds in such amixture may be back-converted to ω-halo-halocumylketone compound ofstructure (10) by treatment with anhydrous hydrogen halide gas.Typically, a solution of the mixture of ω-halo-halocumylketone compoundof structure (10) and α-methylstyrene compounds in a suitable organicsolvent, such as methylene chloride or acetonitrile, is treated with asuitable anhydrous hydrogen halide gas, such as hydrogen chloride. Thereaction is typically treated with the hydrogen halide gas for a periodof time ranging from 30 minutes to 5 hours and at a temperature range offrom 0° C. to room temperature. The remediated ω-halo-halocumylketonecompound of structure (10) may be isolated by evaporation of solvent,but may be stored as a solution in the organic solvent containinghydrogen halide gas.

[0270] In addition, halogen exchange of the benzylic halogen can beaccomplished by thorough solvolysis in the presence of the appropriatehydrogen halide.

[0271] For example, the ω-chloro-halocumylketone compound of structure(10) can be prepared from the ω-bromo-halocumylketone compound ofstructure (10) by thorough aqueous solvolysis in the presence ofhydrogen chloride.

[0272] In step b, the appropriate cyclopropyl cumylketone derivative ofstructure (9) is halogenated to give the corresponding cyclopropylhalocumylketone compound of structure (11) as described previously instep a.

[0273] In step c, the cyclopropyl functionality of the appropriatecyclopropyl halocumylketone compound of structure (11) is ring-opened togive the corresponding ω-halo-halocumylketone compound of structure (10)wherein n=3 as described previously in Scheme A, step j.

[0274] In step d, the appropriate ω-halo ethylphenylketone compound ofstructure (6) is halogenated to give the correspondingω-halo-haloethylphenylketone compound of structure (12) as describedpreviously in step a.

[0275] In step e, the appropriate ω-halo tolylketone compound ofstructure (4) is halogenated to give the corresponding ω-halohalotolylketone compound of structure (13) as described previously instep a.

[0276] In step f, the appropriate cyclopropyl ethylphenylketonederivative of structure (7) is halogenated to give the correspondingcyclopropyl haloethylphenylketone compound of structure (14) asdescribed previously in step a.

[0277] In step g, the appropriate cyclopropyl tolylketone derivative ofstructure (5) is halogenated to give the corresponding cyclopropylhalotolylketone of structure (15) as described previously in step a.

[0278] In step h, the appropriate cyclopropyl halotolylketone ofstructure (15) is ring-opened to give the corresponding ω-halohalotolylketone compound of structure (13) wherein n=3 as describedpreviously in Scheme A, step j.

[0279] In step i, the appropriate cyclopropyl haloethylphenylketonecompound of structure (14) is ring-opened to give the correspondingω-halo-haloethylphenylketone compound of structure (12) wherein n=3 asdescribed previously in Scheme A, step j.

[0280] In addition, the novel intermediates of formula (II), formula(III), formula (IV), formula (V), formula (VI) and formula (VII) whereinR₅ is OH may be prepared by solvolysis of the corresponding novelintermediates of formula (II), formula (III), formula (IV), formula (V),formula (VI) and formula (VII) wherein R₅ is Cl, Br or I, with, forexample, tetrahydrofuran and water or any slightly acidic medium.

[0281] Starting materials for use in Scheme B are readily available toone of ordinary skill in the art.

[0282] The following examples present typical syntheses as described inScheme B. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 4 1-[4-(l-Bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one

[0283] Step a, Method A:

[0284] Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (2.10 g,9.35 mmol) in carbontetrachloride (30 mL), add N-bromosuccinimide (1.75g, 9.83 mmol) and benzoylperoxide (3mg) and stir at reflux for 1 hour.Cool the reaction mixture, filter, wash with water and brine. Dry(MgSO₄), filter and evaporate the solvent in vacuo to give the titlecompound as an amber oil.

[0285] Step a, Method B:

[0286] Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (5.00 g,22.2 mmol) and N-bromosuccinimide (4.1 g, 23.0 mmol) in carbontetrachloride (25 mL) and add AIBN radical initiator (300 mg). Stir andmaintain under a nitrogen atmosphere at 80-90° C. or optionallyirradiate with a sunlamp until a vigorous exotherm occurs at which pointmomentarily remove until reflux subsides and then reapply the heat.Reflux for 30 minutes and add another potion of N-bromosuccinimide (100mg) while maintaining reflux and reflux an additional 15 minutes. Coolto room temperature and precipitate the succinimide from the solution byallowing to stand overnight. Filter and wash the succinimide (2.25 g)with carbon tetrachloride (20 mL). Combine the filtrates and evaporatethe solvent in vacuo to give the title compound as a yellow oil (6.80 g,100%).

[0287]¹H NMR (300 MHz, CDCl₃) δ 7.935 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4Hz, 2H), 3.66 (t, J=6.3 Hz, 2H), 3.16 (t, J=6.8 Hz, 2H), 2.21 (p, J=6.8Hz, 2H), 2.19 (s, 6H); 13C NMR (75 MHz, CDCl₃) 6198.1 (151.63), 135.8,128.0, 126.0, 62.3, 44.5, 35.3, 35.1, 26.7; IR (neat) 2970, 2910, 1680,1675, 1600, 1402, 1225, 1180 cm⁻¹.

[0288] Step a, Method C:

[0289] Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (74.7 g, 333mmol) in methylene chloride (250 mL) and add sodium bromate (17.6 g, 117mmol) in water (75 mL) in a three-necked Morton flask equipped with anoverhead stirrer. Cool the solution to 10° C. and irradiate with two 150W incandescent flood lamps. Add, by dropwise addition, a solution ofsodium bromide (24 g, 233 mmol) and stir for 2 hours. Illuminate foranother 30 minutes, add sodium dithionate (2.0 g), separate the organicphase, dry (MgSO₄) and evaporate the solvent in vacuo to give the titlecompound (100 g, 99%).

[0290] Step a, Method D:

[0291] Dissolve1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (10.4 gassayed at 67% by weight and containing 18wt %1-[4-(2-propene)-phenyl]-4-chloro-butan-1-one) in methylene chloride (50mL) and sparge hydrogen chloride through the solution for 70 minutes.Evaporate the solvent in vacuo to give a 3:1 mixture of1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one and1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (11.6 g).

EXAMPLE 5 (4-Bromomethyl-phenyl)-cyclopropyl-methanone

[0292] Step g: Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (20g, 124 mmol) and 2,2′-Azolons (2-methylpropionitrile) (0.5 g) inmethylene chloride (100 mL and cool to 5° C. Add a suspension ofN-bromosuccinimide (12 g) in methylene chloride (50 mL) and irradiatewith light (150 Watt lamp), maintaining the temperature at 5° C. After2, 3 and 7 hour time periods, add additional N-bromosuccinimide (6 g, 6g, 2.8 g) and continue stirring. After 7.5 hours, wash with water (200mL) and with 0.4M sodium hydrogen carbonate (2×200 mL). Dry (Na₂SO₄),evaporate the solvent in vacuo and recrystallize (hexane) to give thetitle compound as a crystalline solid (26.7 g).

[0293] The following compounds can be prepared by procedures depicted inScheme B:

[0294] [4-(1-bromoethyl)-phenyl]-cyclopropyl-methanone;

[0295] [4-(1-bromo-1-methyl-ethyl)-phenyl]-cyclopropyl-methanone;

[0296] 1-[4-(1-bromomethyl)-phenyl]-4-chloro-butan-1-one; and

1-[4-(1-bromoethyl)-phenyl]-4-chloro-butan-1-one.

[0297] The novel intermediates of formula (VIII) and (IX) and the novelintermediates of formula (II), formula (III), formula (IV), formula (V),formula (VI) and formula (VII) wherein R₅ is Cl, Br or I may also beprepared as described in Scheme C. In Scheme C, all substituents are aspreviously defined unless otherwise indicated.

[0298] Scheme C provides various general synthetic procedures forpreparing the the novel intermediates of formula (VIII) and (IX) andnovel intermediates of formula (II), formula (III), formula (IV),formula (V), formula (VI) and formula (VII) wherein R₅ is Cl, Br or I.

[0299] In step a, the appropriate α-methylstyrene compound of structure(16) is acylated with an appropriate ω-halo compound of the structureHal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the correspondingω-halo-α-methylstyrene compound of structure (17) as describedpreviously in Scheme A, step d.

[0300] In step b, the appropriate α-methylstyrene compound of structure(16) is acylated with an appropriate cyclopropyl compound of thestructure

[0301] wherein B is as previously defined to give the correspondingcyclopropyl α-methylstyreneketone derivative of structure (18) asdescribed previously in Scheme A, step e.

[0302] In step c, the appropriate ω-halo-α-methylstyrene compound ofstructure (17) wherein n=3 is ring-closed to give the correspondingcyclopropyl α-methylstyreneketone derivative of structure (18) asdescribed previously in Scheme A, step k.

[0303] In step d, the appropriate cyclopropyl α-methylstyreneketonederivative of structure (18) is ring-opened to give the correspondingω-halo-α-methylstyrene compound of structure (17) wherein n=3 asdescribed previously in Scheme A, step j.

[0304] In step e, the appropriate ω-halo-α-methylstyrene compound ofstructure (17) is hydrohalogenated to give the correspondingω-halo-halocumylketone derivative of structure (10).

[0305] For example, the appropriate ω-halo-α-methylstyrene compound ofstructure (17) is treated with anhydrous hydrogen halide at atemperature range of from −50° C. to room temperature, preferably 0C -5°C. and for a period of time ranging from 5 minutes to 2 hours. Theω-halo-halocumylketone derivative of structure (10) is recovered fromthe reaction zone by purging with nitrogen.

[0306] In step f, the appropriate ω-halo-halocumylketone derivative ofstructure (10) is dehydrohalogenated to give the correspondingω-halo-α-methylstyrene compound of structure (17) by treatment with baseas is known in the art.

[0307] In step g, the appropriate cyclopropyl α-methylstyreneketonederivative of structure (18) is hydrohalogenated to give thecorresponding cyclopropyl halocumylketone compound of structure (11) asdescribed previously in step e.

[0308] In step h, the appropriate cyclopropyl halocumylketone compoundof structure (11) is dehydrohalogenated to give the correspondingcyclopropyl α-methylstyreneketone derivative of structure (18) asdescribed previously in step f.

[0309] The novel intermediates of formula (II), formula (III), formula(IV), formula (V), formula (VI) and formula (VII) wherein R₅ is CN maybe prepared as described in Scheme D. In Scheme D, all substituents areas previously defined unless otherwise indicated.

[0310] Scheme D provides various general synthetic procedures forpreparing the novel intermediates of formula (II),

[0311] formula (III), formula (IV), formula (V), formula (VI) andformula (VII) wherein R₅ is CN.

[0312] In step a, the appropriate ω-halo-halocumylketone compound ofstructure (10) is cyanated to give the correspondingω-halo-cyanocumylketone compound of structure (19).

[0313] For example, the appropriate ω-halo-cyanocunylketone compound ofstructure (19) may be prepared by reacting an appropriateω-halo-halocumylketone compound of structure (10) with a suitablecyanating agent. Examples of suitable cyanating agents aretrimethylsilyl cyanide, diethylaluminum cyanide and tetrabutylammoniumcyanide, with trimethylsilyl cyanide being preferred. The reaction iscarried out in a solvent, such as methylene chloride, tetrachloroethaneand carbon tetrachloride, with methylene chloride being the preferredsolvent. A catalytic amount of a suitable Lewis acid may also beemployed in the reaction.

[0314] Examples of suitable Lewis acids are boron trichloride, aluminumchloride, titanium tetrachloride, boron trifluoride, tin tetrachlorideand zinc chloride, with tin tetrachloride being preferred. The reactiontime varies from about ½ hour to 8 hours, preferably ½ to 2 hours andthe reaction temperature varies from about 0° C. to room temperature,preferably room temperature. The ω-halo-cyanocumylketone compound ofstructure (16) is recovered from the reaction zone by an aqueous quenchfollowed by extraction as is known in the art. Theω-halo-cyanocumylketone compound of structure (16) may be purified byprocedures well known in the art, such as chromatography andcrystallization.

[0315] In step b, the appropriate ω-halo cumylketone compound ofstructure (8) is cyanated to give the corresponding-halo-cyanocumylketone compound of structure (19).

[0316] For example, the ω-halo-cyanocumylketone compound of structure(19) may be prepared by reacting an appropriate the ω-halo cumylketonecompound of structure (8) with a suitable cyanating agent. Examples ofsuitable cyanating agent are cyanogen chloride, cyanogen bromide andcyanogen iodide, with cyanogen chloride being preferred. The reaction iscarried out according to the procedures outlined by Tanner and Bunce, J.Am. Chem. Soc., 91, 3028 (1969).

[0317] In step c, the appropriate cyclopropyl halocumylketone compoundof structure (11) is cyanated to give the corresponding cyclopropylcyanocumylketone compound of structure (20) as described previously instep a.

[0318] In step d, the appropriate cyclopropyl cumylketone derivative ofstructure (9)-is cyanated to give the corresponding cyclopropylcyanocumylketone compound of structure (20) as described previously instep b.

[0319] In step e, the appropriate ω-halo-haloethylphenylketone compoundof structure (12) is cyanated to give the correspondingω-halo-cyanoethylphenylketone compound of structure (21) as describedpreviously in step a.

[0320] In step f, the appropriate ω-halo-ethylphenylketone compound ofstructure (6) is cyanated to give the correspondingω-halo-cyanoethylphenylketone compound of structure (21) as describedpreviously in step b.

[0321] In step g, the appropriate ω-halo halotolylketone compound ofstructure (13) is cyanated to give the corresponding ω-halocyanotolylketone compound of structure (22) as described previously instep a.

[0322] In step h, the appropriate ω-halo tolylketone compound ofstructure (4) is cyanated to give the corresponding ω-halocyanotolylketone compound of structure (22) as described previously instep b.

[0323] In step i, the appropriate cyclopropyl ethylphenylketone compoundof structure (7) is cyanated to give the corresponding cyclopropylcyanoethylphenylketone compound of structure (23) as describedpreviously in step b.

[0324] In step j, the appropriate cyclopropyl haloethylphenylketonecompound of structure (14) is cyanated to give the correspondingcyclopropyl cyanoethylphenylketone compound of structure (23) asdescribed previously in step a.

[0325] In step k, the appropriate cyclopropyl tolylketone compound ofstructure (5) is cyanated to give the corresponding cyclopropylcyanotolylketone compound of structure (24) as described previously instep b.

[0326] In step 1, the appropriate cyclopropyl halotolylketone ofstructure (15) is cyanated to give the corresponding cyclopropylcyanotolylketone compound of structure (24) as described previously instep a.

[0327] Starting materials for use in Scheme D are readily available toone of ordinary skill in the art.

[0328] The following examples present typical syntheses as described inScheme D. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “0° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 6 Step a:2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-proplonitirile

[0329] Dissolve1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.00 g, 6.59mmol) in anhydrous methylene chloride (20 mL) and place under an argonatmosphere. Add trimethylsilyl cyanide (1.10 mL, 8.25 mmol) followed bytin (IV) chloride (0.20 mL, 1.7 mmol) via syringe. Stir at reflux for 1hour, add water (20 mL) and stir for an additional ½ hour. Separate thelayers and extract the aqueous layer with methylene chloride. Combinethe organic layers, wash with brine, dry (MgSO₄), filter and evaporatethe solvent in vacuo. Purify by silica gel chromatography (15% ethylacetate/hexane) to give the title compound as a white solid; mp 79-80°C.

EXAMPLE 7 Step 1: (4-Cyclopropanecarbonyl-phenyl)-acetonitrile

[0330] Mix (4-bromomethyl-phenyl)-cyclopropyl-methanone (5.0 g, 21mmol), potassium cyanide (2.0 g, 30 mmol), tetra-butylammonium bromide(150 mg), water (5 mL) and acetonitrile (50 mL). Mechanically stir atroom temperature for 3 hours, pour into water (450 mL) and stirovernight. Collect by filtration and recrystallize (hexane) to give thetitle compound as a white crystalline solid; mp 86-87° C.

[0331] The following compounds can be prepared by the syntheticprocedures depicted in Scheme D:

[0332] 2- (4-Cyclopropanecarbonyl-phenyl)-propionitrile;

[0333] 2-(⁴—Cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile;

[0334] [⁴-(4-Chloro-butyryl)-phenyl]-acetonitrile; and

[0335] 2- [4-(4-Chloro-butyryl)-phenyl]-propionitrile.

[0336] The novel intermediates of formula (II), formula (III), formula(IV), formula (V), formula (VI) and formula (VII) wherein R₅ is CN mayalso be prepared as described in Scheme E. In Scheme E, all substituentsare as previously defined unless otherwise indicated.

[0337] Scheme E provides alternative various general syntheticprocedures for preparing the novel intermediates of formula (II),formula (III), formula (IV), formula (V), formula (VI) and formula (VII)wherein R₅ is CN.

[0338] In step a, the appropriate phenylacetonitrile compound ofstructure (25) is methylated to give the corresponding2-cyanoethylbenzene compound of structure (26) as described previouslyin Scheme A, step a.

[0339] Appropriate phenylacetonitrile compounds of structure (25) may beprepared from the corresponding benzyl halide by techniques andprocedures well known by one of ordinary skill in the art and describedpreviously in Scheme D, step a.

[0340] Appropriate benzyl halide compounds may be prepared from thecorresponding toluene derivative of structure (1) as describedpreviously in Scheme B, step a.

[0341] In step b, the appropriate 2-cyanoethylbenzene compound ofstructure (26) is methylated to give the corresponding2-cyano-2-propylbenzene compound of structure (27) as describedpreviously in Scheme A, step a.

[0342] Appropriate 2-cyanoethylbenzene compound of structure (26) may beprepared from the corresponding α-methylbenzyl halide by techniques andprocedures well known by one of ordinary skill in the art and asdescribed previously in step a.

[0343] Appropriate α-methylbenzyl halide compounds may be prepared fromthe corresponding ethylbenzene derivative of structure (2) as describedpreviously in Scheme B, step a.

[0344] In step c, the appropriate phenylacetonitrile compound ofstructure (25) is dimethylated to give the corresponding2-cyano-2-propylbenzene compound of structure (27) as describedpreviously in Scheme A, step c.

[0345] In step d, the appropriate phenylacetonitrile compound ofstructure (25) is acylated with an appropriate ω-halo compound of thestructure Hal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl,Br or I and n is as previously defined to give the corresponding ω-halocyanotolylketone compound of structure (22) as described previously inScheme A, step d.

[0346] In step e, the appropriate phenylacetonitrile compound ofstructure (25) is acylated with an appropriate cyclopropyl compound ofthe structure

[0347] wherein B is as previously defined to give the correspondingcyclopropyl cyanotolylketone compound of structure (24) as describedpreviously in Scheme A, step e.

[0348] In step f, the appropriate 2-cyanoethylbenzene compound ofstructure (26) is acylated with an appropriate ω-halo compound of thestructure Hal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl,Br or I and n is as previously defined to give the correspondingω-halo-cyanoethylphenylketone compound of structure (2 L) as describedpreviously in Scheme A, step d.

[0349] In step g, the appropriate 2-cyanoethylbenzene compound ofstructure (26) is acylated with an appropriate cyclopropyl compound ofthe structure

[0350] wherein B is as previously defined to give the correspondingcyclopropyl cyanoethylphenylketone compound of structure (23) asdescribed previously in Scheme A, step e.

[0351] In step h, the appropriate 2-cyano-2-propylbenzene compound ofstructure (27) is acylated with an appropriate ω-halo compound of thestructure Hal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl,Br or I and n is as previously defined to give the correspondingω-halo-cyanocumylketone compound of structure (19) as describedpreviously in Scheme A, step d.

[0352] Appropriate 2-cyano-2-propylbenzene compound of structure (27)may be prepared from the corresponding α,α-dimethylbenzyl halide bytechniques and procedures well known by one of ordinary skill in the artand as described previously in step a.

[0353] Appropriate α,α-dimethylbenzyl halide compounds may be preparedfrom the corresponding cumene derivative of structure (3) as describedpreviously in Scheme B, step a.

[0354] In step i, the appropriate 2-cyano-2-propylbenzene compound ofstructure (27) is acylated with an appropriate cyclopropyl compound ofthe structure

[0355] wherein B is as previously defined to give the correspondingcyclopropyl cyanocumylketone compound of structure (20) as describedpreviously in Scheme A, step e.

[0356] In step j, the cyclopropyl functionality of the appropriatecyclopropyl cyanotolylketone compound of structure (24) is ring-openedto give the corresponding ω-halo cyanotolylketone compound of structure(22) wherein n=3 as described previously in Scheme A, step j.

[0357] In step k, the appropriate ω-halo cyanotolylketone compound ofstructure (22) wherein n=3 is ring-closed to give the correspondingcyclopropyl cyanotolylketone compound of structure (24) as describedpreviously in Scheme A, step k.

[0358] In step 1, the cyclopropyl functionality of the appropriatecyclopropyl cyanoethylphenylketone compound of structure (23) isring-opened to give the corresponding ω-halo-cyanoethylphenylketonecompound of structure (21) wherein n=3 as described previously in SchemeA, step j.

[0359] In step m, the appropriate ω-halo-cyanoethylphenylketone compoundof structure (21) wherein n=3 is ring-closed to give the correspondingcyclopropyl cyanoethylphenylketone compound of structure (23) asdescribed previously in Scheme A, step k.

[0360] In step n, the cyclopropyl functionality of the appropriatecyclopropyl cyanocumylketone compound of structure (20) is ring-openedto give the corresponding ω-halo-cyanocumylketone compound of structure(19) wherein n=3 as described previously in Scheme A, step j.

[0361] In step o, the appropriate ω-halo-cyanocumylketone compound ofstructure (19) is ring-closed to give the corresponding cyclopropylcyanocumylketone compound of structure (20) as described previously inScheme A, step k.

[0362] In step p, the appropriate ω-halo-cyanoethylphenylketone compoundof structure (21) is methylated to give the correspondingω-halo-cyanocumylketone compound of structure (19) as describedpreviously in Scheme A, step a.

[0363] In step q, the appropriate cyclopropyl cyanotolylketone compoundof structure (24) is dimethylated to give the corresponding cyclopropylcyanocumylketone compound of structure (20) as described previously inScheme A, step c.

[0364] In step r, the appropriate ω-halo cyanotolylketone compound ofstructure (22) is methylated to give the correspondingω-halo-cyanoethylphenylketone compound of structure (21) as describedpreviously in Scheme A, step a.

[0365] In step s, the appropriate ω-halo cyanotolylketone compound ofstructure (22) is dimethylated to give the correspondingω-halo-cyanocumylketone compound of structure (19) as describedpreviously in Scheme A, step c.

[0366] In step t, the appropriate cyclopropyl cyanoethylphenylketonecompound of structure (23) is methylated to give the correspondingcyclopropyl cyanocumylketone compound of structure (20) as describedpreviously in Scheme A, step a.

[0367] In step u, the appropriate cyclopropyl cyanotolylketone compoundof structure (24) is methylated to give the corresponding cyclopropylcyanoethylphenylketone compound of structure (23) as describedpreviously in Scheme A, step a.

[0368] Starting materials for use in Scheme E are readily available toone of ordinary skill in the art.

[0369] The following examples present typical syntheses as described inScheme E. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 8 Step c: Cumyl Cyanide

[0370] Place phenylacetonitrile (92.3 mL, 0.800 mol), tetran-butylammonium chloride (4.45 g of a 50% solution, 8.0 mmol) and 50%aqueous sodium hydroxide solution (2.874 mole NaOH) into a 3-neckround-bottom flask, with a thermowell, overheard stirrer, refluxcondenser with a dry-ice/acetone trap and a sparge tube. Heat to 40-70C. with stirring at 115 RPM (paddle stir blade), and bubble in methylchloride gas (11.7 g, 0.232 mole) over a 30 minute period. Turn off themethyl chloride addition and heat and stir overnight. Sparge additionalmethyl chloride (35.4 g, 0.700 mol) into the reaction mixture (heated to35 C.) over a period of 2 hours. Stir the resulting mixture at ambienttemperature for 22 hours and sparge additional methyl chloride (39.5 g,0.781 mol) into the reaction mixture at a temperature of 40-70 C.(mostly at 55-60 C.). Sparge additional methyl chloride (8.7 g, 0.172mol) into the reaction mixture and allow to cool to 30 C. Remove thecondenser and add deionized water (250 mL) and heptane (250 mL).Transfer to a separatory funnel and draw off the aqueous (bottom) layer.Wash the remining organic layer with fresh water (2×100 mL), evaporatethe solvent in vacuo to give a dark red oil.

[0371] Add the oil, 50% aqueous sodium hydroxide (79 g, 0.988 mole) andtetra n-butylammonium chloride (1.0 g, 3.6 mmol) to a 500 mL 3-neckedround bottom flask with a magnetic stir bar. Using the same experimentalprocedure described above, sparge in methyl chloride. Heat to 40-60 C.,stir and sparge in methyl chloride (20.59, 0.40 mole) over 1 hour. Allowthe reaction mixture to cool, add deionized water (100 g) and stir.Allow the layers to settle and remove the bottom layer by pipet. Repeatwash with additional water (10 g) to give the title compound as a darkorange oil (111.0 g, wet with water).

EXAMPLE 9 Step q:2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile

[0372] Dissolve potassium t-butoxide (2.429, 21.6 mmol) in diglyme (8mL), cool to 10° C. and slowly add with mechanical stirring, a solutionof (4-cyclopropanecarbonyl-phenyl)-acetonitrile (2 g, 10.8 mmol) andmethyl iodide (1.5 mL, 24.0 mmol) in diglyme (10 mL). After 10 minutes,add additional potassium t-butoxide (0.3 g, 2.6 mmol) in diglyme (2 mL)and stir for a total of 45 minutes. Pour into a mixture of water (100mL) and ethyl acetate (50 mL) and adjust the pH to 1.5-2 with dilutehydrochloric acid. Separate the organic phase and extract the aqueousphase with ethyl acetate (50 mL). Combine the organic phases and washwith brine (2×100 mL). Dry (Na₂SO₄), evaporate the solvent in vacuo andrecrystallize (ethyl ether/hexane) to give the title compound as ayellow solid; mp 80-82° C.

[0373] The following compounds can be prepared by procedures depicted inScheme E:

[0374] (4-Cyclopropanecarbonyl-phenyl)-acetonitrile;

[0375] 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-proplonitirile;

[0376] 2-(4-Cyclopropanecarbonyl-phenyl)-propionitrile;

[0377] [4-(4-Chloro-butyryl)-phenyl)-acetonitrile; and

[0378] 2-[4-(4-Chloro-butyryl)-phenyl]-propionitrile.

[0379] The novel intermediates of formula (II), formula (III), formula(IV), formula (V), formula (VI) and formula (VII) wherein R₅ is COOalkylmay also be prepared as described in Scheme F. In Scheme F, allsubstituents are as previously defined unless otherwise indicated.

[0380] Scheme F provides alternative various general syntheticprocedures for preparing the novel intermediates of formula (II),formula (III), formula (IV), formula (V), formula (VI) and formula (VII)wherein R₅ is COOalkyl.

[0381] In step a, the appropriate phenylacetic acid ester compound ofstructure (28) is methylated to give the correspondingα-methylphenylacetic acid ester compound of structure (29) as describedpreviously in Scheme A, step a.

[0382] Appropriate phenylacetic acid ester compounds of structure (28)are prepared from the corresponding phenylacetic acid compounds bystandard esterification reactions which are well known by one ofordinary skill in the art.

[0383] Appropriate phenylacetic acid compounds may be prepared byhydrolysis of the corresponding phenylacetonitrile compounds ofstructure (25) by techniques and procedures well known and appreciatedby one of ordinary skill in the art, such as base hydrolysis.Alternatively, the phenylacetic acid compounds may be prepared byelectrochemical carboxylation of the corresponding benzyl halide asdescribed in Scheme H, step h.

[0384] In step b, the appropriate α-methylphenylacetic acid estercompound of structure (29) is methylated to give the correspondingα,α-dimethylphenylacetic acid ester compound of structure (30) asdescribed previously in Scheme A, step a.

[0385] Alternatively α-methylphenylacetic acid ester compound ofstructure (29) are prepared for the corresponding α-methylphenylaceticacid compounds by standard esterification reactions which are well knownby one of ordinary skill in the art as described in step a.

[0386] Appropriate α-methylphenylacetic acid compounds may be preparedby hydrolysis of the corresponding 2-cyanoethylbenzene compound ofstructure (26) as described previously in step a. Alternatively, theα-methylphenylacetic acid compounds may be prepared by electrochemicalcarboxylation of the corresponding α-methylbenzyl halide as described inScheme H, step h.

[0387] In step c, the appropriate phenylacetic acid ester compound ofstructure (28) is dimethylated to give the correspondingα,α-dimethylphenylacetic acid ester compound of structure (30) asdescribed previously in Scheme A, step c.

[0388] Alternatively α,α-dimethylphenylacetic acid ester compound ofstructure (30) are prepared for the correspondingα,α-dimethylphenylacetic acid compounds by standard esterificationreactions which are well known by one of ordinary skill in the art adescribed in step a.

[0389] Appropriate α,α-dimethylphenylacetic acid compounds may beprepared by hydrolysis of the corresponding 2-cyano-2-propylbenzenecompound of structure (27) as described previously in step a.Alternatively, the α,α-dimethylphenylacetic acid compounds may beprepared by electrochemical carboxylation of the correspondingα,α-dimethylbenzyl halide as described in Scheme H, step h. Appropriateα,α-dimethylbenzyl halide compounds may be prepared by hydrohalogenationof the corresponding α-methylstyrene as described previously in SchemeC, step e.

[0390] In step d, the appropriate phenylacetic acid ester compound ofstructure (28) is acylated with an appropriate ω-halo compound of thestructure Hal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl,Br or I and n is as previously defined to give the correspondingω′-halo-α′-keto-phenylacetic acid ester compound of structure (34) asdescribed previously in Scheme A, step d.

[0391] In step e, the appropriate phenylacetic acid ester compound ofstructure (28) is acylated with an appropriate cyclopropyl compound ofthe structure

[0392] wherein B is as previously defined to give the correspondingcyclopropylketo-phenylacetic acid ester compound of structure (33) asdescribed previously in Scheme A, step e.

[0393] In step f, the appropriate α-methylphenylacetic acid estercompound of structure (26) is acylated with an appropriate ω-halocompound of the structure Hal—(CH₂)_(n)—C(═O)—B, wherein B is Hal orhydroxy, Hal is Cl, Br or I and n is as previously defined to give thecorresponding ω′-halo-α′-keto-α-methylphenylacetic acid ester compoundof structure (30) as described previously in Scheme A, step d.

[0394] In step g, the appropriate α-methylphenylacetic acid estercompound of structure (29) is acylated with an appropriate cyclopropylcompound of the structure

[0395] wherein B is as previously defined to give the correspondingcyclopropylketo-α-methylphenylacetic acid ester compound of structure(35) as described previously in Scheme A, step e.

[0396] In step h, the appropriate α,α-dimethylphenylacetic acid estercompound of structure (30) is acylated with an appropriate ω-halocompound of the structure Hal—(CH₂)_(n)—C(═O)—B, wherein B is Hal orhydroxy, Hal is Cl, Br or I and n is as previously defined to give thecorresponding ω′-halo-α′-keto-α,α-di-methylphenylacetic acid estercompound of structure (31) as described previously in Scheme A, step d.

[0397] Appropriate α,α-dimethylphenylacetic acid ester compound ofstructure (30) are prepared for the correspondingα,α-dimethylphenylacetic acid compounds by standard esterificationreactions which are well known by one of ordinary skill in the art asdescribed in step a.

[0398] Appropriate α,α-dimethylphenylacetic acid compounds may beprepared by hydrolysis of the corresponding 2-cyano-2-propylbenzenecompound of structure (27) as described previously in step a.

[0399] In step i, the appropriate α,α-dimethylphenylacetic acid estercompound of structure (30) is acylated with an appropriate cyclopropylcompound of the structure wherein B is as previously defined to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid estercompound of structure (32) as described previously in Scheme A, step e.

[0400] In step j, the appropriate ω′-halo-α′-keto-α-methylphenylaceticacid ester compound of structure (33) is methylated to give thecorresponding ω′-halo-α′-keto-α,α-di-methylphenylacetic acid estercompound of structure (32) as described previously in Scheme A, step a.

[0401] In step k, the cyclopropyl functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) is ring-opened to give the correspondingω′-halo-α′-keto-α,α-di-methylphenylacetic acid ester compound ofstructure (31) wherein n=3 as described previously in Scheme A, step j.

[0402] The resulting ω′-halo-α′-keto-α,α-di-methylphenylacetic acidester compound of structure (31) wherein n=3 may be purified bydistillation and/or crystallization.

[0403] In step 1, the appropriateω′-halo-α′-keto-α,α-di-methylphenylacetic acid ester compound ofstructure (31) wherein n=3 is ring-closed to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) as described previously in Scheme A, step k.

[0404] The resulting cyclopropylketo-α,α-dimethylphenylacetic acid estercompound of structure (32) may be purified by distillation and/orcrystallization. Additional cyclopropylketo-α,α-dimethylphenylaceticacid ester compound of structure (32) may be recovered from the motherliquors of the crystallization by distillation.

[0405] Alternatively, additionalω′-halo-α′-keto-α,α-di-methylphenylacetic acid ester compound ofstructure (31) wherein n=3 may be recovered from the mother liquors ofthe crystallization by ring-closure as described in step 1 to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid estercompound of structure (32), purifyingcyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) by distillation, ring-opening the purifiedcyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) as described previously in step k to give the purifiedω′-halo-α′-keto-α,α-di-methylphenylacetic acid ester compound ofstructure (31).

[0406] In step m, the appropriate ω′-halo-α′-keto-phenylacetic acidester compound of structure (34) is dimethylated to give thecorresponding ω′-halo-α′-keto-α,α-di-methylphenylacetic acid estercompound of structure (31) as described previously in Scheme A, step c.

[0407] In step n, the appropriate ω′-halo-α′-keto-phenylacetic acidester compound of structure (34) is methylated to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) as described previously in Scheme A, step a.

[0408] In step o, the cyclopropyl functionality of the appropriatecyclopropylketo-α-methylphenylacetic acid ester compound of structure(35) is ring-opened to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) wherein n=3 as described previously in Scheme A, step j.

[0409] In step p, the appropriate ω′-halo-α′-keto-α-methylphenylaceticacid ester compound of structure (33) wherein n=3 is ring-closed to givethe corresponding cyclopropylketo-α-methylphenylacetic acid estercompound of structure (35) as described previously in Scheme A, step k.

[0410] In step q, the appropriate cyclopropylketo-α-methylphenylaceticacid ester compound of structure (35) is methylated to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid estercompound of structure (32) as described previously in Scheme A, step a.

[0411] In step r, the appropriate cyclopropylketo-phenylacetic acidester compound of structure (36) is dimethylated to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid estercompound of structure (32) as described previously in Scheme A, step c.

[0412] In step s, the cyclopropyl functionality of the appropriatecyclopropylketo-phenylacetic acid ester compound of structure (36) isring-opened to give the corresponding ω′-halo-α′-keto-phenylacetic acidester compound of structure (34) wherein n=3 as described previously inScheme A, step j.

[0413] In step t, the appropriate ω′-halo-α′-keto-phenylacetic acidester compound of structure (34) wherein n=3 as is ring-closed to givethe corresponding cyclopropylketo-phenylacetic acid ester compound ofstructure (36) as described previously in Scheme A, step k.

[0414] In step u, the appropriate cyclopropylketo-phenylacetic acidester compound of structure (36) is methylated to give the correspondingcyclopropylketo-α-methylphenylacetic acid ester compound of structure(35) as described previously in Scheme A, step a.

[0415] Starting materials for use in Scheme F are readily available toone of ordinary skill in the art.

[0416] The following examples present typical syntheses as described inScheme F. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 10 Step c: 2-Methyl-2-phenylpropionate, methyl ester

[0417] Equip a two liter, 3-necked, round bottom flask with a thermowellwith a thermometer, heating mantle, mechanical agitator, gas inlet forMeCl, rubber septum for sampling by syringe and a cryoscopic condensingsystem. The condensing system is composed of an 18 inch inner helicalcoil/outer jacket condenser chilled to −50 C. with refrigerated acetonetopped with a dry ice cold finger having approximately 100 square inchesof chilled surface area. The cold finder is vented through a drying tubefilled with drying agent and MeCl is supplied from a lecture bottlemounted on a digital balance. The feed rate can be accurately controlledusing a needle valve and monitored by rotomter. The rotometer iscalibrated with MeCl to give an average response of 2.5 mg/min/scaledivision. Phenylacetic acid, ethyl ester is supplied via {fraction(1/16)} inch stainless steel tubing inserted through the rubber samplingseptum by a HPLC pump from a 1 liter bottle mounted on a digitalbalance. The bottle is sealed with a septum and vented through a dryingtube filled with drying agent. The temperature is controlled using athermowatch to regulate the heating mantle. If cooling is required, itis accomplished either by immersing the reaction flask in a water bathor simply by removing the mantle.

[0418] The phenylacetic acid, ethyl ester pump is primed withphenylacetic acid containing 1 st % t-butanol and the phenylacetic acid,ethyl ester balance is zeroed. The MeCl balance is zoned and a 200 gsample of 60% NaH is weighed into a wide mouth plastic jar in a nitrogenfilled glove bag and is transferred to the reaction vessel through afunnel (sampling septum is removed). Through the same funnel is addedanhydrous glyme (800 mL) and the septum (pierced by the {fraction(1/16)} inch phenylacetic acid, ethyl ester feed tube) is replaced. Themixture is agitated and heated to 50 C. while MeCl (40 g) is introduced.When the reaction mixture reaches 50 C., the continuous addition ofphenylactic acid, ethyl ester/t-butanol at 1 mL/min and MeCl atapproximately 0.62 g/min. is initiated. Samples of about p.1 mL arewithdrawn at intervals using a disposable syringe fitted with an 8 inchneedle. A portion of the sample (5-15 drops depending on theaccumulation of product) is dissovled in 25% aqueous acetonitrile (5 mL)and analyzed immediately. The reaction is continued for an additional 2hours at 50 C. and then at ambient temperature overnight.

[0419] In the apparatus described above, agitate NaH (180 g of 60%) andanhydrous glyme (800 mL) and heat to 50 C. Add MeCl (52 g) along withmethyl phenylacetate (20 g). Stir for 1 hour at 50 C., then add, bycontinuous addition, methyl phenylacetate (0.8 mL/min) and MeClγapproximately 0.53 g/min). Stir for 1 hour, stop the additoina andcontinue heating for 1.5 hours. Resume the additions and run for 45minutes. Allow to agitate at ambient temperature overnight. Heat thereaction to 50 C. and resume the addition of methyl phenylacetate (0.4mL/min) and MeCl (approximately 0.27 g/min). When a total of 246 g ofmethyl phenylacitate has been added, stop the addition and agitateovernight. Distill the glyme at 1 atm. until the pot temperature reaches125 C. Cool the residue and pour into water (1 L) containing acetic acid(100 mL). Filter through filter aid and separate the phases. Distill theorganic phase through a 10-plate Oldershaw column fitted with a refluxsplitting head at 4mm Hg. Collect 10 mL at a 5:2 reflux ratio anddiscard. Collect the title compound at a 2:1 reflux ratio and headtemperature of 93 C. (10 g).

EXAMPLE 11 Step d: [4-(4-Chloro-butyryl)-phenyl]-acetic acid, ethylester and [3-(4-Chloro-butyryl)-phenyl]-acetic acid, ethyl ester

[0420] Method A: Load a 3-neck flask with sublimed AlCl₃ (293 g, 2.08mmol) and heptane (400 mL). Cool to below 5° C. and slowly addchlorobutyryl chloride (125 mL), keeping the temperature below 5° C. Addphenylethyl acetate (160 mL), keeping the temperature below 10° C. andstir overnight. Decant the heptane layer and dissolve the residue inmethylene chloride (400 mL). Slowly pour the methylene chloride solutioninto a mixture of concentrated hydrochloric acid (200 mL) and crackedice. Separate the organic phase, wash with water (1 L), followed by 5%sodium hydrogen carbonate (1 L). Evaporate the solvent in vacuo to givea red oil (243 g).

[0421] Dissolve the red oil (243 g) in methylene chloride (250 mL) andsparge with hydrogen chloride gas for 1.5 hours and evaporate thesolvent in vacuo to give the title compound as a 50:50 mixture of paraand meta isomers (243 g). Method B: Place aluminum chloride (293 g) andmethylene chloride (300 mL) in a 1 L, 3-neck round bottom flask with athermowell and equipped with a thermomter, mechanical stirrer, refluxcondenser, equilibrating dropping funnel and ice bath. Cool to 10 C. andadd, by dropwise addition, 4-chlorobutyryl chloride (169 g), keeping thetemperature below 10 C. After addition is complete, add, by dropwiseaddition, phenylethyl acetate (164 g), keeping the temperature below 10C. Heat the reaction to 40 C. for 16 hours, slowly pour into amechanically agistated 4 L beaker containing ice/water (2000 g) and stirfor 1 hour. Separate the layers, extract the water phase with methylenechloride (50 mL), filter the combined organic phases through a ¼ inchthick bed of filter aid and extract eequentially with water (100 mL) and10 wt % Na2CO3 (200 mL). Re-extract the cargbonate solution with freshmethylene chloride (50 mL) and wash the combined methylene chloridesolutions with water (100 mL). Distill off solvent at atmosphericpressure until the pot temperature reaches 120 C. Cool the residue anddilute with 2 B absolute ethanol (200 mL). Heat the solution to 70 C.and sparge in anhydrous HCl (20 g) over 10 minutes. After 40 minutes,cool the reaction and hold overnight under nitrogen. Evaporate thesolvent in vacuo to give the title compound (258 g).

EXAMPLE 12 Step k: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionicacid, ethyl ester

[0422] Method A: Dissolve2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester(100 g) in xylene (500 mL) and ethanol (100 mL) and heat to 70° C.Sparge the atmosphere of the reaction with hydrogen chloride gas (24.6g) over 220 hours. Evaporate the solvent in vacuo to give the titlecompound.

[0423] Method B: Add a solution of 5M HCl in acetonitrile (50 mL, 9 g ofHCl, 247 mmol) to 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionicacid, ethyl ester (25.5 g, 98 mmol) and seal in a 100 mL flask with arubber septum. Heat to 50° C. for 4 hours, dilute with toluene (50 mL),wash with water (50 mL), aqueous 10% Na2CO3 (50 mL) and then water (50mL). Evaporate the solvent in vacuo to give the title compound as an oil(27.2 g).

[0424] Method C: Place2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester(86 g, 330 mmol) and dry acetonitrile (70 mL) in a 250 mL 3-neckround-bottom flask equipped with a magnetic stirbar, thermometoer, gasinlet and distillation head connected to a balloon by way of a T fittingfor pressure control. Slowly warm the reaction mixture with stirring to60° C. while sparging excess HCl into the reaction mixture for 6 hours,dilute with toluene (50 mL), wash with water (50 mL), aqueous 10% Na2CO3(50 mL) and then water (50 mL). Evaporate the solvent in vacuo to givethe title compound.

[0425] Method D: Place2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester(91 g, 350 mmol) in a 1 L 3-neck round-bottom flask equipped with amagnetic stirbar, thermometer, gas inlet, and distillation headconnected to a balloon by way of a T fitting for pressure control.Slowly sparge in anhydrous HCl, keeping the balloon slightly inflated.After 10 minutes, add acetonitrile (590 mL), heat to 65° C. and addexcess HCl over 7 hours. Heat the mixture and remove acetonitrile/HCloverhead. After 500 mL of acetonitrile is removed, add mixed xylene (200mL) and continue the distillation. Add additional xylene (200 m) andafter a total of 640 mL of solvent has been removed (pot=130° C. andoverhead=130° C.), add ethanol 2 B (100 mL). Remove the ethanol bydistillation to give the title compound as a oil (330 g).

[0426] Method E: Place2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester(98 g, 410 mmol) and xylenes (600 mL) in a 1 L 3-neck round-bottom flaskequipeed with a magnetic stirbar, thermomoter, gas inlet anddistillation head connected to a balloon by way of a T fitting forpressure control. Heat the reaction mixture to 80° C. and slowly spargein anhydrous HCl. After 100 minutes, add ethanol 2B (100 mL) and HCl (26g) and heat to 35° C. for 2 hours. Remove the ethanol and HCl bydistillation with aspirator vacuum (pot=35° C., overhead=30° C.) to givethe title compound as a solution in xylene.

[0427] Method F: Place2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester(500 g) in a 4 L Hastelloy reactor equipped with a gas inlet, overheadstirrer, temperature control and dip pipe for sampling. Heat the oil to60 C. and evacuate the head space. Add HCl raising the pressure to 10psig and react for 80-300 minutes. Vent the excess HCl and sparge theoil with nitrogen for 5 minutes to give the title compound.

[0428] Method G: Fit a 2 L 3-neck round bottom flask with an overheadpaddle stirrer, a gas sparge tube (with fritted end to disperse gas) anda reflux condenser (with drying tube on top, filled with drying agent).Fit the bottom of the flask with a heating mantle and put2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester(78.10 g, 0.300 mol), xylenes (400 mL) and absolute 2B ethanol (90 mL)into the flask. Stir to dissolve all the solids at ambient temperature.Sparge hydrogen chloride from a lecture bottle (38.36 g, 1.052 mol) intothe stirred solution without external heating over a 15 minute period.Replace the sparge tube with a glass stopper and heat the solution bymantle, with stirring, at 40-79 C. for 45 minutes and 79 C. for 15minutes. Replace the reflux condenser with a simple still head fittedwith a thermometer and condenser. Collect 200 mL of distillate (80-138C. at atmospheric pressure) and allow the remaining light yellowsolution to cool to give a mixture of the title compound and xylenes.

EXAMPLE 13 Step t: (4-Cyclopropanecarbonyl-phenyl)-acetic acid, ethylester and (3—Cyclopropanecarbonyl-phenyl)-acetic acid, ethyl ester

[0429] Dissolve the mixture of [4-(4-chloro-butyryl)-phenyl]-aceticacid, ethyl ester and [3-(4-chloro-butyryl)-phenyl]-acetic acid, ethylester (650 g) in 2B ethanol (1250 mL). Add, by dropwise addition, asolution of 2 B ethanolic KOH (168 g in 1000 mL), keeping thetemperature below 10 C. After the addition, stir magnetically for 5hours at −10 C. Bring the mixture to pH 6 with acetic acid (5 mL) andfilter through a celite pre-coat. Evaporate the solvent in vacuo to givethe title compound as an oil (538 g).

EXAMPLE 14 Step d: [4-(4-Chloro-butyryl)-phenyl]-acetic acid,2-ethylhexyl ester

[0430] Mix 2-ethyl-1-hexanol (6.5 g, 5 mol), triethylamine (50.5 g, 0.5mol) and methylene chloride (50 mL). Add, by dropwise addition,2-phenylacetyl chloride (5 mol) and warm to 50° C. Stir at roomtemperature overnight, filter and wash the filtercake with methylenechloride (50 mL). Combine the organic phases and wash with 5% aqueoushydrochloric acid (50 mL) and water. Dry (MgSO₄), evaporate the solventin vacuo and purify by distillation to give 2-phenylacetic acid,2-(2-ethylhexy)l ester.

[0431] Mix chlorobutyryl chloride (16.9 g) and AlCl₃ (29.3 g) at roomtemperature. Add 2-phenylacetic acid, 2-ethylhexyl-ester (27.6 g),keeping the temperature below 10° C. Heat at 35° C. for 24 hours, quenchin ice water (200 g). Separate the organic phase, dry (MgSO₄) andevaporate the solvent in vacuo. Dilute the residue with ethanol (150mL), add hydrogen chloride (5 g) and heat to 75° C. After 2.5 hours, addanother 5 g of hydrogen chloride and stir at 75° C. for 24 hours.Evaporate the solvent in vacuo to give the title compound.

EXAMPLE 15 Step h: 2-[4-(4-Chloro-butyrl)-phenyl]-2-methyl-proprionicacid, ethyl ester and 2-[3-(4-Chloro-butyrl)-phenyl]-2-methyl-proprionicacid, ethyl ester

[0432] Method A: Place aluminum chloride (58.4 g, 438 mmol) andmethylene chloride (100 mL) in a 250 mL 3 neck flask equipped with acondenser, thermometer, and overhead stirrer. Cool to 10 C. and add, bydropwise addition, 4-chlorobutyryl chloride (32.4 g, 230 mmol), keepingthe temperature below 10 C. Add, by dropwise addition, ethyldimethylphenylacetate (40 g, 208 mmol) at 10 C. After the addition,slowly warm the mixture to room temperature and then heat at reflux for17 hours. Quench the reaction into ice (400 g) and stir for 1 hour.Extract with methylene chloride (2×25 mL), wash with water (25 mL), 10%aqueous sodium carbonate (25 mL) and water (25 mL). Evaporate thesolvent in vacuo to give a red oil γ58.7 g).

[0433] Dissolve the red oil (58.7 g) in 2 B ethanol (40 mL) and place ina 250 mL round bottom flask equipped with an overhead stirrer,condenser, thermometer and gas inlet tube. Add anhydrous HCl (3 g. 80mmol) with vigorous stirring and heat to 70 C. for 1 hour. Evaporate thesolvent in vacuo to give the title compound as a yellow oil (59 g).

[0434] Method B: Place AlCl₃ (146.5 g. 1.1 mol) and methylene chloride(75 mL) in a 3-neck, 500 mL round-bottomed flack equipped with anoverhead stirrer, bottom drop valve, thermometer, condenser andtemperature control and cool to 15° C. Add, by dropwise addition,4-chlorobutyryl chloride (84.5 g, 0.6 mol), keeping the temerature below15° C. Add, by dropwise addition, ethyl 2-methyl-2-phenylpropionate (96g, 0.5 mol), keeping the temperature below 15° C. After addition iscomplete, stir the reaction mixture at 22° C. for 1 hour, then heat atreflux (57° C.) for 2 hours. Add the reaction mixture, by dropwiseaddition, by way of the bottom drop valve, to water (500 mL) at 95° C.contained in a 2 L 3 neck flask equipped with a magnetic stirbar,thermometer and distillation head. During addition, hold the reactionmixture at 70° C. by allowing the methylene chloride to distilloverhead. After the quench is complete, separate the the organic layer,dry (MgSO₄) and evaporate the solvent in vacuo to give the titlecompound (150 g).

EXAMPLE 16 Step h: 2-[4-(4-Chloro-butyrl)-phenyl]-2-methyl-proprionicacid, methyl ester

[0435] Method A: Mix AlCl₃ (128 g) and methylene chloride (66 mL) andcool with a dry ice/acetone bath to −15 C. Add, by dropwise addition,4-chlorobutyryl chloride (73.8 g), keeping the temperature below 15 C.Add, by dropwise addition, methyl 2-methyl-2-phenylpropionate (77.8 g),keeping the temperature below 15 C. After addition is complete, stirethe reaction mixture at 22 C. for 10 minutes, then heat to 45 C. for 3hours. Quench into ice/water (875 g), filter through filter aid,separate the layers and wash the aqueous phase with methylene chloride(50 mL). Combine the organics and evaporate the solvent in vacuo to give131 g. Decant solids off and place the oil? in a 500 mL 3-neck flaskalong with methanol (150 mL). Purge with HCl and heat at reflux for 1hour and allow to stand overnight. Evaporate the solvent in vacuo,dissolve in methylene chloride (250 mL), wash with water (200 mL) andNaHCO3 (300 mL). Evaporate the solvent in vacuo to give a mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (approximately m:p 50:50) (121 g).

[0436] Place the mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (approximately m:p 50:50) (40.1 g) in a 250 mL, 3-necked flaskwith a mechanical agitator, N₂ blanket and cooling bath. Add methanol(80 mL) at room temperature and cool to −5 C. with and ice/acetone/waterbath. Seed with 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,methyl ester and allow to stand at −5 C. for 1 hour. Cool to −10 C. withice/acetone and allow to stand for 1.5 hours. Cool to −16 C. and holdfor 30 minutes. Vacuum filter through a 60 mL sintered glass jacketedfilter funnel chilled to −10 C. Wash the filtercake with cold (−50 C.)methanol (30 mL) and cold (−50 C.) n-pentane (30 mL). Dry the filtercakebriefly in a stream of nitrogen and vacuum dry (20 C. at 15 mm Hg) togive the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionicacid, methyl ester and2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester(approximately m:p 10:90) (10.5 g).

[0437] Dissolve the mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (approximately m:p 10:90) in methanol (30 mL), cool to 10 C. in anice/water bath and seed with2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester.Cool to 0 C. and hold for 20 minutes. Vacuum filter, wash and dry asabove to give the title compound (5.6 g) as an off-white solid; mp29.5-30.5 C.

[0438] Method B: Mix AlCl₃ (128 g) and methylene chloride (66 mL) andcool with a dry ice/acetone bath to −15 C. Add, by dropwise addition,4-chlorobutyryl chloride (73.8 g), keeping the temperature below 15 C.Add, by dropwise addition, methyl 2-methyl-2-phenylpropionate (77.8 g),keeping the temperature below 15 C. After addition is complete, stirethe reaction mixture at 22 C. for 10 minutes, then heat to 45 C. for 3hours. Quench into ice/water (875 g), filter through filter aid,separate the layers and wash the aqueous phase with methylene chloride(50 mL). Combine the organics and evaporate the solvent in vacuo to give131 g. Decant solids off and place the oil in a 500 mL 3-neck flaskalong with methanol (150 mL). Purge with HCl and heat at reflux for 1hour and allow to stand overnight. Evaporate the solvent in vacua,dissolve in methylene chloride (250 mL), wash with water (200 mL) andNaHCO₃ (300 mL). Evaporate the solvent in vacuo to give a mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (121 g) (approximately 50:50 m:p).

[0439] Place the mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (approximately 50:50 m:p) (40.1 g) in a 250 mL, 3-necked flaskwith a mechanical agitator, N₂ blanket and cooling bath. Add methanol(80 mL) at room temperature and cool to −5 C. with and ice/acetone/waterbath. Seed with 2-(4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,methyl ester and allow to stand at −5 C. for 1 hour. Cool to −10 C. withice/acetone-and allow to stand for 1.5 hours. Cool to −16 C. and holdfor 30 minutes. Vacuum filter through a 60 mL sintered glass jacketedfilter funnel chilled to −10 C. Wash the filtercake with cold (−50 C.)methanol (30 mL) and cold (−50 C.) n-pentane (30 mL). Dry the filtercakebriefly in a stream of nitrogen and vacuum dry (20 C. at 15 mm Hg) togive the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionicacid, methyl ester and2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester(approximately 10:90 m:p) (10.5 g).

[0440] To the methanol solution of the mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (approximately 50:50 m:p) (approximately 70:30 m:p) fromcrystallization (i.e. mother liquor), slowly add 1 to 1.2 euivalents of25% NaOMe/MeOH solution. Agitate for approximately 30 minutes at 25 C.Neutralize the excess NaOMe with excess carbon dioxide. Add water (300mL) per mole of subtrate, evaporate the methanol by vacuum distiallationand decant the aqueous layer to give a mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximately 70:30 m:p).

[0441] Distill the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximately 70:30 m:p) at 0.5mm Hg and discard a light fractionboiling at 25-130 C. (pot temp −105-165 C.). Continue distilling the oilat 0.5mm Hg and collect a second fraction boiling at 130-150 C. (pottemperature 165-190) to give the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximately 70:30 m:p)

[0442] Pack a 31/32 in. I.D. vacuum jacked and silvered column with 53inches of 1 in. diameter, 316 stainless steel packing. For hightemperature distillation, the column is fitted with an adiabatic jacketcomposed of an inner layer of 1 in. fiber glass wrapped with heat tapein an upper and lower zone and finally covered with 2 in. fiber glassinsulation. The upper zone is heated at 135 C. and the lower zone at 185C. The magnetic reflux splitting head is controlled by a reflux timerand fitted with a standard thermometer for monitoring overheadtemperature. Vacuum is supplied by a system composed of a pump protectedby a dry ice trap and fitted with a McLeod gage for monitoring theoverhead pressure. The 1 L distillation pot is heated with an electricmantel at 65 volts, agitated magnetically and fitted with a mercurymanometer for monitoring bottoms pressure, and a thermocouple formonitoring bottoms temperature.

[0443] The still pot is charged with 265 g each of m- and p-xylene andfitted with a rubber septum for sampling by syringe. The xylene mixtureis heated at total reflux-and atmosphere pressure with the temperature135 C. at the head and 139 C. in the bottoms. Samples are withdrawn foranalysis by collecting a few drops of distillate and extracting about 1mL from the pot. The still is sampled after 3 hours and again after 18hours for calibration by GC and theoretical plate calculations using theFenske correlation and a relative volatility, α=1.0209.

[0444] Charge the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximately 70:30 m:p) to the still pot and neat at totalreflux until the column has equilibrated. Take a forecut at 2:1 refluxratio and increase the reflux ratio to 5:1 and -the2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterstripped. Cool and release vacuum and allow to sit overnight. Addbis(2-ethylhexyl)phthalate (dioctyl phthalate) (100 mL) to the still potand restart the still as before. Once the still has equilibrated,collect mixed fractions of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester at 50:50 reflux ratio.

[0445] Place the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximatelty m:p 50:50) (330 mmol) and dry acetonitrile (70 mL)in a 250 mL 3-neck round-bottom flask equipped with a magnetic stirbar,thermometoer, gas inlet and distillation head connected to a balloon byway of a T fitting for pressure control. Slowly warm the reactionmixture with stirring to 60° C. while sparging excess HCl into thereaction mixture for 6 hours, dilute with toluene (50 mL), wash withwater (50 mL), aqueous 10% Na2CO3 (50 mL) and then water (50 mL).Evaporate the solvent in vacuo to give the mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (121 g) (approximately 50:50 m:p).

[0446] Place the mixture of2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl esterand 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methylester (approximately 50:50 m:p) (40.1 g) in a 250 mL, 3-necked flaskwith a mechanical agitator, N₂ blanket and cooling bath. Add methanol(80 mL) at room temperature and cool to −5 C. with and ice/acetone/waterbath. Seed with 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid,methyl ester and allow to stand at −5 C. for 1 hour. Cool to −10 C. withice/acetone and allow to stand for 1.5 hours. Cool to −16 C. and holdfor 30 minutes. Vacuum filter through a 60 mL sintered glass jacketedfilter funnel chilled to −10 C. Wash the filtercake with cold (−50 C.)methanol (30 mL) and cold (−50 C.) n-pentane (30 mL). Dry the filtercakebriefly in a stream of nitrogen and vacuum dry (20 C. at 15 mm Hg) togive the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionicacid, methyl ester and2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester(approximately 10:90 m:p) (10.5 g). Dissolve the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methylester (approximately 10:90 m:p) in methanol (30 mL), cool to 10 C. in anice/water bath and seed with2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester.Cool to 0 C. and hold for 20 minutes. Vacuum filter, wash and dry asabove to give the title compound (5.6 g) as an off-white solid; mp29.5-30.5 C.

EXAMPLE 17 Step 1: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionicacid, ethyl ester

[0447] Dissolve a mixture of2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethyl esterand 2-[3-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethylester (599) in 2 B ethanol (100 mL) and add, by dropwise addition, asolution of KOH (49.49 of 85%) in 2 B ethanol (250 mL), keeping thetemperature below 15 C. After the addition, warm the reaction mixture toroom temperature and stir magentically for 1 hour. Bring to pH 6 withacetic acid and filter through a celite pre-coat. Evaporate the solventin vacuo to give a mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester as an oil (57.1 g) Purify by one of the following methods:

[0448] Method A: Pack a 31/32 in. I.D. vacuum jacked and silvered columnwith 53 inches of 1 in. diameter, 316 stainless steel packing. For hightemperature distillation, the column is fitted with an adiabatic jacketcomposed of an inner layer of 1 in. fiber glass wrapped with heat tapein an upper and lower zone and finally covered with 2 in. fiber glassinsulation. The upper zone is heated at 135 C. and the lower zone at 185C. The magnetic reflux splitting head is controlled by a reflux timerand fitted with a standard thermometer for monitoring overheadtemperature. Vacuum is supplied by a system composed of a pump protectedby a dry ice trap and fitted with a McLeod gage for monitoring theoverhead pressure. The 1 L distillation pot is heated with an electricmantel at 65 volts, agitated magnetically and fitted with a mercurymanometer for monitoring bottoms pressure, and a thermocouple formonitoring bottoms temperature.

[0449] The still pot is charged with 265 g each of m- and p-xylene andfitted with a rubber septum for sampling by syringe. The xylene mixtureis heated at total reflux and atmosphere pressure with the temperature135 C. at the head and 139 C. in the bottoms. Samples are withdrawn foranalysis by collecting a few drops of distillate and extracting about 1mL from the pot. The still is sampled after 3 hours and again after 18hours for calibration by GC and theoretical plate calculations using theFenske correlation and a relative volatility, α=1.0209.

[0450] Charge the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester (901.2 g) to the still pot and heat at total reflux until thecolumn has equilibrated. Take a forecut at 2:1 reflux ratio and increasethe reflux ratio to 5:1 and the2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterstripped. Cool and release vacuum and allow to sit overnight. Addbis(2-ethylhexyl)phthalate (dioctyl phthalate) (100 mL) to the still potand restart the still as before. Once the still has equilibrated,collect mixed fractions of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester at 10:1 reflux ratio. Once the overheads are free of2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterby GC analysis, reduce the reflux ratio to 2:1 and collect the titlecompound.

[0451] Method B: Place crude mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand-2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester (4872 g) on a rotary evaporator and strip of vaolatives to an endpoint of 85 C., 15 mm to give a brown oil (4006 g). Charge a 3 L roundbottom three neck flask equipped with magnetic stirbar, thermometer anddistillation head with stripped crude mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester. Distill the oil at 0.5 mm Hg and discard a light fraction boilingat 25-130 C. (pot temp -105-165 C., 9.5 g). Continue distilling the oilat 0.5 mm Hg and collect a second fraction boiling at 130-150 C. (pottemperature 165-190, 3217 g).

[0452] Place the crude flash distilled product (1000 g) in a 4 LHastelloy reactor equipped with Camille control along with water (500mL) and ethanol 2 B (2 L). CHeat the mixture to 40 C. while agitating at400 rpm. Set the reactor jacket to cool the contents at approximately 12C./hour to a final temperature of 0 C. after a clear solution isobserved. Then set the jacket to cool the reactor contents atapproximately 12 C./hour to a final temperature of −15 C. and hold atthat temperature for more than one hour. Filter the slurry, wash withcold (−15 C.) ethanol, cold heptanes (−15 C.) and dry to give a solid(507 g). Purify by recrystallization from mixed heptanes as above togive the title compound (503 g) after drying.

[0453] Recycle: Pack a 31/32 in. I.D. vacuum jacked and silvered columnwith 53 inches of 1 in. diameter, 316 stainless steel packing. For hightemperature distillation, the column is fitted with an adiabatic jacketcomposed of an inner layer of 1 in. fiber glass wrapped with heat tapein an upper and lower zone and finally covered with 2 in. fiber glassinsulation. The upper zone is heated at 135 C. and the lower zone at 185C. The magnetic reflux splitting head is controlled by a reflux timerand fitted with a standard thermometer for monitoring overheadtemperature. Vacuum is supplied by a system composed of a pump protectedby a dry ice trap and fitted with a McLeod gage for monitoring theoverhead pressure. The 1 L distillation pot is heated with an electricmantel at 65 volts, agitated magnetically and fitted with a mercurymanometer for monitoring bottoms pressure, and a thermocouple formonitoring bottoms temperature.

[0454] The still pot is charged with 265 g each of m- and p-xylene andfitted with a rubber septum for sampling by syringe. The xylene mixtureis heated at total reflux and atmosphere pressure with the temperature135 C. at the head and 139 C. in the bottoms. Samples are withdrawn foranalysis by collecting a few drops of distillate and extracting about 1mL from the pot. The still is sampled after 3 hours and again after 18hours for calibration by GC and theoretical plate calculations using theFenske correlation and a relative volatility, α=1.0209.

[0455] Charge the still pot with the mother liquors from thecrystllization of the mixture of2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester (759 g, 14.7 wt % p-isomer). Distill as described above to give510 g overhead at a 5:1 reflux ratio (0.2 mm bottom pressure, 7-13 mmoverhead pressure, 182-205 C. bottom temperature, 92-144 C. overheadtemperature). Save the bottoms (214 g, 52wt % p-isomer) for recycle.Charge a 250 ml round bottom flask equipped with a distillation head,thermometer, and magnetic stirbar with 190 g of the saved bottoms fromabove. Flash distill, retaining the fraction boiling at 149-165 C. (0.6mm, pot temperature=159-190 C.) to give 178 g (50.5% p-isomer). Mixflash distilled material (981 g) with material obtained from the recycleflash distillation (108 g) to give 1100 g of recycle material forcrystallization. Crystallize 92.5 g (94 wt % p-isomer) from 25%water-ethanol to give the title compound (39.7 g) after drying.

EXAMPLE 18 Step h and step 1:2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl esterand 2-(3—Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethylester

[0456] Method A: Place aluminum chloride (586 g, 4.4 moles) andmethylene chloride (300 mL) in a 2 L 3-neck round bottom flask equippedwith an overhead stirrer, dry ice condenser, and nitrogen atmosphere.Cool to 10 C. and add, by dropwise addition, chlorobutyryl chloride (338g, 2.4 moles), keeping the temperature below 15 C. After addition iscomplete, add, by dropwise addition, ethyl 2-methyl-2-phenylpropionate(384 g, 2 mol), keeping the temperature below 15 C. After addition wascomplete, warm the reaction mixture to 22 C. and stir for 1 hour. Raisethe temperature to 90 C., stir for 90 minutes, cool to room temperatureand slowly pounr into a 6 L stirred flask containing ice/water (4 kg).Filter through a celite precoat, separate the organic phase and wash theaqueous phase with methylene chloride (50 mL). Evaporate the solvent invacuo to give a mixture of2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethyl esterand 2-[3-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethylester.

[0457] Dissolve the mixture of2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethyl esterand 2-[3-(4-chloro-butyryl)-phenyl]-2-methyl-proprionic acid, ethylester in 2 B ethanol (400 mL) and place in a 3 L 3-neck round bottomflask equipped with an overhead stirrer, gas inlet and reflux condenser.Add anhydrous HCl (50 g) and sitr the mixture at 70 C. for 1 hour. Coolthe solution to 15 C. and add, by dropwise addition, aqueous 50% NaOH(260 g), keeping the temperature below 15 C. After the addition, stirthe mixture an addition 1 hour at 22 C. Add toluene (700 mL) followed byacetic acid (2 g) and then water (500 mL). Separate the layers andevaporate the solvent in vacuo to give the title compuond as a yellowoil (551 g).

[0458] Method B: Place aluminum chloride (458 g, 3.4 mole) and methylenechloride (234 mL) in a 2 L 3nck round bottom flask equipped with anoverhead stirrer, dry ice condenser and nitrogen atmosphere. Cool to 10C. and add, by dropwise addition, 4-chlorobutyryl chloride (264 g, 1.9mol), keeping the temperature below 15 C. After addition is complete,add, by dropwise addition, ethyl 2-methyl-2-phenylpropionate (300 g,1.56 mol), keeping the temperature below 15 C. After the addition iscomplete, warm the reaction mixture to 24 C. and stir for 1 hour. Raisethe temperature to 57 C. for 2 hours, cool to room temperature andslowly pour into a 6 L stirred flask containing ice/water (3.1 kg).Filter through a celite precoat and separate the phases. Evaporate thesolvent in vacuo to give an oil.

[0459] Dissolve the oil in 2 B ethanol (312 mL) and place in a 3 L 3neck round bottom flask equiped with an overhead stirrer, gas inlet andreflux condenser. Add anhydrous HCl (39 g) and stir the mixture at 70 C.for 1 hour. Cool to 50 C. and add, by dropwise addition, aqueous 20%NaOH (641 g), keeping the temperature below 50 C. After the addition,stir the mixture for an additional 1 hour at 50 C., cool to roomtemperature and neutralize with acetic acid (6.25 g). Separate thelayers and evaporate the solvent in vacuo to give the title compound(391 g).

EXAMPLE 19 Step h and step 1:2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, 2-ethylhexylester

[0460] Mix methylene chloride (50 mL), 2-ethylhexyl alcohol (130 g, 1mol) and triethylamine (50 g, 0.5 mol). Add, by dropwise addition, ethyldimethylphenylacetyl chloride (91 g, 0.5 mol). Heat the reaction mixtureto 68 C. for 1 hour, add methylene chloride (100 mL) and stir overnight.Remove the solids by filtration, wash with methylene chloride (50 mL),combine with the liquid organics, wash with aqueous 5% HCl, (50 mL),water (50 mL) and dry over MgSO4. Evaporate the solvent in vacuo andpurify by distillation (119 C. at 1 mmHg) (105 g, 76%).

[0461] Place aluminum chloride (29.3 g) and methylene chloride (30 mL)in a 250 mL round bottom flask with an overhead stirrer, temperaturecontrol, condenser, additonal funnel and nitrogen atmosphere. Add, bydropwise addition, chlorobutyryl chloride (16.9 g), keeping thetemperature below 10 C. After addition is complete, warm the reactionmixture to 36 C. and hold for 24 hours. Quench the reaction mixture intoice/water (200 g) and extract with methylene chloride (50 mL). Wash theorganics with water (50 mL) and dry (MgSO4). Evaporate the solvent invacuo to give an oil (30 g). Place the oil in a 250 mL flask equippedwith an overhead stirrer, gas inlet, condenser and thermometer. Add 2 Bethanol (150 mL) followed by anhydrous HCl (5 g). Heat the reactionmixture to 76 C. for 2.5 hours then add additional HCl (5 g). Heat thereaction mixture at 76 C. for 22 hours, evaporate the solvent in vacuoto give an oil. Dissolve the oil in 2 B ethanol (100 mL), treat withsolid KOH (10 g) and heat at reflux for 2 hours.

EXAMPLE 20 Step m and step 1:2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, ethyl ester

[0462] Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-acetic acid, ethyl ester(28.5 g) in toluene (50 mL) and evaporate the solvent in vacuo to removetraces of ethanol. Dissolve the residue in diglyme (50 mL) and add, bydropwise addition, to a suspension of sodium hydride (12.2 g of a 60%suspension in mineral oil) slurried in diglyme (150 mL) containingmethyl chloride (log). Slowly add methyl chloride (log) and stir for 15minutes. Filter through filter aid, wash filtercake with acetonitrileand evaporate the solvent. Remove meta-isomer by distillation (150° C. @1 mm) and crystallize (ethanol) to give the title compound (93%).

EXAMPLE 21 Step f and step : 2-(4-Cyclopropanecarbonyl-phenyl)-propionicacid, ethyl ester and 2-(3—Cyclopropanecarbonyl-phenyl)-propionic acid,ethyl ester

[0463] Dissolve 2-phenylpropionic acid (30 g) in 2 B ethanol (100 mL andadd anhydrous HCl (10 g). Allow to sit for 48-72 hours, evaporate thesolvent in vacuo and purify by distillation to give ethyl2-phenylpropionate (31 g); bp 100 C. at 6 mmm. Place aluminum chloride(49.4 g, 0.371 mole) and methylene chloride (50 mL) in a 250 mL 3-neckround bottom flask equipped with an overhead stirrer, addition funneland thermometer. Cool to less then 10 C. and add, by dropwise addition,chlorobutyrylchloride (23.8 g, 0.202 mol), keeping the temperature below10 C. After addition is complete, add, by dropwise addition, ethyl2-phenylpropianate (30 g, 0.17 mol), keeping the temperature below 10 C.Stir at room temperature for 1 hour then heat at reflux for 14 hours.Quench into ice/water (350 g) and filter through a celite pre-coat.Separate the layers and evaporate the solvent in vacuo to give a redoil.

[0464] Dissolve the red oil in 2 B ethanol (35 mL) and place in a roundbottom flask with a condenser and gas inlet. Add anhydrous HCl (4.3 g)and heat the solution to 70 C. for 1 hour. Cool the solution to 10 C.and add, by dropwise addition, 20% aqueous sodium hydroxide. Separatethe layers and evaporate the solvent in vacuo to give an oil.

[0465] Re-treat the oil with HCl in 2 B ethanol as above, cool to 10 C.and treat with a 20% solution of sodium ethoxide in ethanol. Neutralizewith acetic acid, filter the solids and evaporate the solvent in vacuo.Purify by distillation to give the title compound; bp 161-167 at 1.2 mm.

[0466] The novel intermediates of formula (II), formula (III), formula(IV), formula (V), formula (VI) and formula (VII) wherein R₅ is CONR₆R₇may also be prepared as described in Scheme G. In Scheme G, allsubstituents are as previously defined unless otherwise indicated.

[0467] Scheme G provides alternative various general syntheticprocedures for preparing the novel intermediates of formula (II),formula (III), formula (IV), formula (V), formula (VI) and formula (VII)wherein R₅ is CONR₆R₇.

[0468] In step a, the appropriate phenylacetic acid amide compound ofstructure (37) is methylated to give the correspondingα-methylphenylacetic acid amide compound of structure (38) as describedpreviously in Scheme A, step a.

[0469] Appropriate phenylacetic acid amide compound of structure (37)are prepared from the corresponding phenylacetic acid by standardamide-forming reactions as are known in the art. The appropriatephenylacetic acids may be prepared by hyrdolysis of the corresponding2-cyano-2-propylbenzene compound of structure (27) by techniques andprocedures well known and appreciated by one of ordinary skill in theart.

[0470] In step b, the appropriate α-methylphenylacetic acid amidecompound of structure (38) is methylated to give the correspondingα,α-dimethylphenylacetic acid amide compound of structure (39) asdescribed previously in Scheme A, step a.

[0471] Appropriate α-methylphenylacetic acid amide compound of structure(38) are prepared from the corresponding α-methylphenylacetic acid bystandard amide-forming reactions as are known in the art as as describedin step a.

[0472] In step c, the appropriate phenylacetic acid amide compound ofstructure (37) is dimethylated to give the correspondingα,α-dimethylphenylacetic acid amide compound of structure (39) asdescribed previously in Scheme A, step c.

[0473] In step d, the appropriate phenylacetic acid amide compound ofstructure (37) is acylated with an appropriate ω-halo compound of thestructure Hal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl,Br or I and n is as previously defined to give the correspondingω′-halo-α′-keto-phenylacetic acid amide compound of structure (43) asdescribed previously in Scheme A, step d.

[0474] In step e, the appropriate phenylacetic acid amide compound ofstructure (37) is acylated with an appropriate cyclopropyl compound ofthe structure

[0475] wherein B is as previously defined to give the correspondingcyclopropylketo-phenylacetic acid amide compound of structure (45) asdescribed previously in Scheme A, step e.

[0476] In step f, the appropriate α-methylphenylacetic acid amidecompound of structure (38) is acylated with an appropriate W-halocompound of the structure Hal—(CH₂)_(n)—C(═O)—B, wherein B is Hal orhydroxy, Hal is Cl, Br or I and n is as previously defined to give thecorresponding ω′-halo-α′-keto-α-methylphenylacetic acid amide compoundof structure (42) as described previously in Scheme A, step d.

[0477] In step g, the appropriate α-methylphenylacetic acid amidecompound of structure (38) is acylated with an appropriate cyclopropylcompound of the structure

[0478] wherein B is as previously defined to give the correspondingcyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) as described previously in Scheme A, step e.

[0479] In step h, the appropriate α,α-dimethylphenylacetic acid amidecompound of structure (39) is acylated with an appropriate ω-halocompound of the structure Hal—(CH₂)_(n)—C(═O)—B, wherein B is Hal orhydroxy, Hal is Cl, Br or I and n is as previously defined to give thecorresponding ω′-halo-α′-keto-α,α-di-methylphenylacetic acid amidecompound of structure (40) as described previously in Scheme A, step d.

[0480] Appropriate α,α-dimethylphenylacetic acid amide compound ofstructure (39) are prepared from the correspondingα,α-dimethylphenylacetic acid by standard amide-forming reactions as areknown in the art as as described in step a.

[0481] In step i, the appropriate α,α-dimethylphenylacetic acid amidecompound of structure (39) is acylated with an appropriate cyclopropylcompound of the structure

[0482] wherein B is as previously defined to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) as described previously in Scheme A, step e.

[0483] In step j, the appropriate ω′-halo-α′-keto-α-methylphenylaceticacid amide compound of structure (42) is methylated to give thecorresponding ω′-halo-α′-keto-α,α-di-methylphenylacetic acid amidecompound of structure (40) as described previously in Scheme a, step a.

[0484] In step k, the cyclopropyl functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) is ring-opened to give the correspondingω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (40) wherein n=3 as described previously in Scheme A, step j.

[0485] In step 1, the appropriateω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (40) wherein n=3 is ring-closed to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) as described previously in Scheme A, step k.

[0486] In step m, the appropriate ω′-halo-α′-keto-phenylacetic acidamide compound of structure (43) is dimethylated to give thecorresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acid amidecompound of structure (40) as described previously in Scheme A, step c.

[0487] In step n, the appropriate ω′-halo-α′-keto-phenylacetic acidamide compound of structure (43) is methylated to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid amide compound of structure(42) as described previously in Scheme A, step a.

[0488] In step o, the cyclopropyl functionality of the appropriatecyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) is ring-opened to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid amide compound of structure(42) wherein n=3 as described previously in Scheme A, step j.

[0489] In step p, the appropriate ω′-halo-α′-keto-α-methylphenylaceticacid amide compound of structure (42) wherein n=3 is ring-closed to givethe corresponding cyclopropylketo-α-methylphenylacetic acid amidecompound of structure (44) as described previously in Scheme A, step k.

[0490] In step q, the appropriate cyclopropylketo-α-methylphenylaceticacid amide compound of structure (44) is methylated to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid amidecompound of structure (41) as described previously in Scheme A, step a.

[0491] In step r, the appropriate cyclopropylketo-phenylacetic acidamide compound of structure (45) is dimethylated to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid amidecompound of structure (41) as described previously in Scheme A, step c.

[0492] In step s, the cyclopropyl functionality of the appropriatecyclopropylketo-phenylacetic acid amide compound of structure (45) isring-opened to give the corresponding ω′-halo-α′-keto-phenylacetic acidamide compound of structure (43) wherein n=3 as described previously inScheme A, step j.

[0493] In step t, the appropriate ω′-halo-α′-keto-phenylacetic acidamide compound of structure (43) wherein n=3 is ring-closed to give thecorresponding cyclopropylketo-phenylacetic acid amide compound ofstructure (45) as described previously in Scheme A, step k.

[0494] In step u, the appropriate cyclopropylketo-phenylacetic acidamide compound of structure (45) is methylated to give the correspondingcyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) as described previously in Scheme A, step a.

[0495] Starting materials for use in Scheme G are readily available toone of ordinary skill in the art.

[0496] The following example present typical syntheses as described inScheme G. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 22 Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionicacid, N-methoxy-N-methylamide

[0497] Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) intoluene (80 mL) and add, by dropwise addition over 5 minutes, thionylchloride (15 mL, 206 mmol). Stir at room temperature overnight, addadditional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1hour. Remove excess thionyl chloride by azeotropic distillation withtoluene (40 mL). Add toluene (20 mL) to the reaction mixture along witha solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL).Add, by dropwise addition, a solution of N,O-dimethylhydroxylaminehydrochloride (8.9 g, 91.2 mmol) in water (20 mL) without cooling andstir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slowaddition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate theorganic layer and wash with aqueous HCl (2N, 75 mL), saturated sodiumhydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer over(Na₂SO₄), filter, evaporate the filtrate in vacuo and purify by vacuumdistillation to give 2-methyl-2-phenyl-propionic acid,N-methoxy-N-methylamide (18.0 g, 95%); bp 91-103° C./5 mm Hg. MS (CI,CH₄) m/e 208 (M⁺+1, 100), 119.

[0498] Slurry AlCl₃ (10.15 g, 76.1 mmol) and methylene chloride (45 mL)under a nitrogen atmosphere at room temperature. Add 4-chlorobutyrylchloride (4.27 mL, 38.1 mmol), stir for 20 minutes and add, by dropwiseaddition over 10 minutes, a solution of 2-methyl-2-phenyl-propionicacid, N-methoxy-N-methylamide (6.58 g, 31.7 mmol) in methylene chloride(15 mL). Stir at room temperature for 45 minutes, then heat at 30-35° C.for 7 hours. Pour into ice water (150 mL) and separate the layers. Washthe aqueous layer with water (3×75 mL), combine the aqueous layers andextract with methylene chloride (2×75 mL). Combine the organic layersand dry (Na₂SO₄). Filter, evaporate the filtrate in vacuo and purify bysilica gel chromatography (3:1 hexane/ethyl acetate) give the titlecompound (6.19 g, 63%) as a light yellow oil.

[0499] MS (CI,CH₄) m/e 312 (M⁺+1), 276.

EXAMPLE 23 Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionicacid, dimethylamide

[0500] Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) intoluene (80 mL) and add, by dropwise addition over 5 minutes, thionyl-chloride (15 mL, 206 mmol). Stir at room temperature overnight, addadditional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1hour. Remove excess thionyl chloride by azeotropic distillation withtoluene (40 mL). Add toluene (20 mL) to the reaction mixture along witha solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL).Add, by dropwise addition, a 40% aqueous solution of dimethylaminehydrochloride (20 mL, 0.18 mol) without cooling and stir for 2 hours.Add tert-butylmethyl ether (75 mL) following by slow addition of aqueousHCl (2N, 75 mL) with vigorous stirring. Separate the organic layer andwash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate(25 mL) and brine (50 mL). Dry the organic layer over (Na₂SO₄), filter,evaporate the filtrate in vacuo and purify by crystallization to give2-methyl-2-phenyl-propionic acid, dimethylamide (15.35 g, 88%) as awhite solid; mp 57-59° C.

[0501] Anal. Calcd for C₁₂H₁₇No: C, 75.35; H, 8.96; N, 7.32; Found: C,75.12; H, 8.86; N, 7.26.

[0502] Add AlCl₃ (1.12 g, 8.40 mmol) to carbon tetrachloride (6 mL)under a nitrogen atmosphere at room temperature. Add 4-chlorobutyrylchloride (0.49 mL, 4.37 mmol), stir for 15 minutes and add, by dropwiseaddition over 3 minutes, a solution of 2-methyl-2-phenyl-propionic acid,dimethylamide (0.64 g, 3.36 mmol) in carbon tetrachloride (6 mL). Stirat room temperature for 17 hours, dilute with methylene chloride (10mL), pour into ice water (50 mL) and separate the layers. Wash theaqueous layer with methylene chloride (2×70 mL), 5% aqueous sodiumhydrogen carbonate, combine the organic layers and dry (Na₂SO₄). Filter,evaporate the filtrate in vacuo and purify by silica gel chromatography(5:2 hexane/ethyl acetate) to give the title compound (0.72 g, 72%) as alight yellow oil.

EXAMPLE 24 Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionicacid pyrrolidineamide

[0503] Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) intoluene (80 mL) and add, by dropwise addition over 5 minutes, thionylchloride (15 mL, 206 mmol). Stir at room temperature overnight, addadditional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1hour. Remove excess thionyl chloride by azeotropic distillation withtoluene (40 mL). Add tolune (20 mL) to the reaction mixture along with asolution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL).Add, by dropwise addition, pyrrolidine (7.61 mL, 91 mmol) withoutcooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL)following by slow addition of aqueous HCl (2N, 75 mL) with vigorousstirring. Separate the organic layer and wash with aqueous HCl (2N, 75mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Drythe organic layer over (Na₂SO₄), filter, evaporate the filtrate in vacuoand purify by crystallization to give 2-methyl-2-phenyl-propionic acid,pyrrolidineamide (18.28 g, 92%) as a solid; mp 96-97° C.

[0504] Anal. Calcd for C₁₄Hl₉NO: C, 77.38; H, 8.81; N, 6.45; Found: C,77.21; H, 8.70; N, 6.41.

[0505] Add AlCl₃ (8.31 g, 62.3 mmol) to carbon tetrachloride (65 mL)under a nitrogen atmosphere at room temperature. Add 4-chlorobutyrylchloride (03.5 mL, 31.2 mmol), stir for 15 minutes and add, by dropwiseaddition over 15 minutes, a solution of 2-methyl-2-phenyl-propionicacid, pyrrolidineamide (5.64 g, 26.0 mmol) in carbon tetrachloride (60mL). Stir at room temperature for 17 hours, pour into ice water (100 mL)and separate the layers. Wash the aqueous layer with methylene chloride(2×70 mL), 5% aqueous sodium hydrogen carbonate, combine the organiclayers and dry (Na₂SO₄). Filter, evaporate the filtrate in vacuo andpurify by silica gel chromatography (5:2 hexane/ethyl acetate) to givethe title compound (6.55 g, 78%) as a light yellow oil.

EXAMPLE 25 Step 1: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionicacid, N-methoxy-N-methylamide

[0506] Add potassium hydroxide (13 g) to2-[4-(4-chloro-butyryl-phenyl]-2-methyl-propionamide,N-methoxy-N-methylamide (96.6 mmol) and stir at room temperature for 40minutes, filter and wash the filtercake with ethanol. Evaporate theethanol in vacuo, dissolve in methylene chloride (100 mL), wash withwater (50 mL), 5% sodium hydrogen carbonate (50 mL) and water (50 mL).Evaporate the solvent in vacuo, removing water with toluene azeotrope.Purify the product by distillation followed by recrystallization(heptane) to give the title compound (7.4 g).

[0507] The following compounds can be prepared by procedures depicted inScheme G:

[0508] (4-cyclopropanecarbonyl-phenyl)-acetic acid,N-methoxy-N-methylamide;

[0509] (4-cyclopropanecarbonyl-phenyl)-acetic acid, dimethylamide;

[0510] (4-cyclopropanecarbonyl-phenyl)-acetic acid, pyrrolidineamide;

[0511] 2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid,N-methoxy-N-methylamide;

[0512] 2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid, dimethylamide;

[0513] 2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid,pyrrolidineamide;

[0514] 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid,N-methoxy-N-methylamide;

[0515] 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid,dimethylamide;

[0516] 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid,pyrrolidineamide;

[0517] [4-(4-Chloro-butyryl)-phenyl]-acetic acid,N-methoxy-N-methylamide;

[0518] [4-(4-Chloro-butyryl)-phenyl]-acetic acid, dimethylamide;

[0519] [4-(4-Chloro-butyryl)-phenyl]-acetic acid, pyrroldineamide;

[0520] 2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid,N-methoxy-N-methylamide;

[0521] 2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, dimethylamide;

[0522] 2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, pyrroldineamide;

[0523] 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid,N-methoxy-N-methylamide;

[0524] 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic aciddimethylamide;

[0525] 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid,pyrroldineamide;

[0526] The novel intermediates of formula (II), formula (III), formula(IV), formula (V), formula (VI) and formula (VII) wherein R₅ is COOH,COOalkyl or CONR₆R₇ may be prepared as described in Scheme H. In SchemeH, all substituents are as previously defined unless otherwiseindicated.

[0527] Scheme H provides various general synthetic procedures forpreparing the novel intermediates of formula (II), formula (III),formula (IV), formula (V), formula (VI) and formula (VII) wherein R₅ isCOOH, COOalkyl or CONR₆R₇.

[0528] In step a, the nitrile functionality of the appropriateω-halo-cyanocumylketone compound of structure (19) is converted to thecorresponding ester by reaction with an appropriate C₁ to C₆ alcohol togive the corresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound of structure (31).

[0529] For example, the ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound of structure (31) may be prepared by reacting anappropriate ω-halo-cyanocumylketone compound of structure (19) with anappropriate C₁-C₆ alcohol in the presence of a suitable anhydrous acidfollowed by treatment with water. Examples of appropriate alcohols aremethanol, ethanol, propanol, and the like, with methanol beingpreferred. Examples of appropriate acids are hydrogen chloride andhydrogen bromide, with hydrogen chloride being preferred. The reactiontime varies from about ½ hour to 48 hours, preferably 3 to 5 hours andthe reaction temperature varies from about −20° C. to room temperature,preferably −10° C. to 0° C. The ω′-halo-α′-keto-α,α-dimethylphenylaceticacid ester compound of structure (28) is recovered from the reactionzone by evaporation of the solvent followed by extraction as is known inthe art. The ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound of structure (31) may be purified by procedures well known inthe art, such as chromatography.

[0530] In step b, the nitrile functionality of the appropriateω-halo-cyanocumylketone compound of structure (19) is converted to thecorresponding amide to give the ω′-halo-α′-keto-α,α-dimethylphenylaceticacid amide compound of structure (40) wherein R₆ and R₇ are bothhydrogen.

[0531] For example, hydrolysis may be achieved by using a suitable acid,such as concentrated hydrochloric acid as is known in the art.

[0532] In step c, the carboxy ester functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (31) is hydrolyzed to give the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure(46).

[0533] For example, hydrolysis may be achieved by using a suitablenon-nucleophilic base, such as sodium methoxide in methanol as is knownin the art. Other methods known in the art for ester cleavage includepotassium carbonate in methanol, methanolic ammonia, potassiumcarbonate, potassium hydroxide, calcium hydroxide, sodium hydroxide,magnesium hydroxide, sodium hydroxide/pyridine in methanol, potassiumcyanide in ethanol and sodium hydroxide in aqueous alcohols, withpotassium hydroxide being preferred. The reaction is typically carriedout in an aqueous lower alcohol solvent, such as methanol, ethanol,isopropyl alcohol, n-butanol, 2-ethoxyethanol or ethylene glycol orpyridine, at temperatures ranging from room temperature to the refluxtemperature of the solvent, and the reaction time varies from about ½hour to 100 hours.

[0534] In step d, the carboxy functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)may be esterified by techniques and procedures well known andappreciated by one of ordinary skill in the art to give thecorresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound of structure (31).

[0535] For example, one such method involves reacting an appropriateω-halo-α′-keto-a,-dimethylphenylacetic acid compound of structure (46)with an excess of an appropriate C₁-C₆ alcohol which is straight orbranched in the presence of a small amount of mineral acid, such ashydrochloric acid or sulfuric acid, hydrochloric acid being preferred,at reflux. Another suitable method involves reacting an appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)with an excess of diazomethane in a suitable solvent such as ether atroom temperature to give the methyl ester. In addition, theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (28) may also be prepared by reacting an appropriateω′-halo-α′-keto-α,α-di-methylphenylacetic acid compound of structure(46) with an excess of 2,2-dimethoxypropane in a suitable solvent suchas methanol at 0° C. to room temperature to give the methyl ester.Another suitable method involves first reacting an appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)with thionyl chloride in a suitable solvent such as methylene chlorideto give an intermediate acid chloride, followed by addition of asuitable C₁ to C₆ alcohol which is straight or branched. Anothersuitable method involves the alkylation of the carboxylate anion with anappropriate electrophile, such as dimethyl sulfate or ethyl bromide, togive the corresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound of structure (31). Such methods are well known in the artand are described in J.Org.Chem., 29, 2490-2491 (1964).

[0536] Alternatively, step k and step d may be combined and theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (34) wherein n=3 may be prepared from the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure(50).

[0537] Alternatively, step p, step k and step d may be combined and theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (31) wherein n=3 may be prepared from the correspondingcyclopropyl cyanocumylketone compound of structure (20).

[0538] In step e, the nitrile functionality of the appropriateω-halo-cyanocumylketone compound of structure (19) is converted to thecorresponding carboxy to give theω′-halo-α′-keto-α,α-dimethylphenylaceticα′-keto-α,α-dimethylphenylacetic acid compound of structure (46).

[0539] For example, hydrolysis may be achieved by using a suitable acid,such as concentrated hydrochloric acid as is known in the art.

[0540] In step f, the amide functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid amide compound ofstructure (40) is converted to the corresponding acid by acid hydrolysisas is known in the art to give the correspondingω′-halo-α′-keto-α,α--dimethylphenylacetic acid compound of structure(46).

[0541] For example, hydrolysis may be achieved by using a suitablenon-nucleophilic base, such as sodium methoxide in methanol as is knownin the art. Other methods known in the art for ester cleavage includepotassium carbonate in methanol, methanolic ammonia, potassiumcarbonate, potassium hydroxide, calcium hydroxide, sodium hydroxide,magnesium hydroxide, sodium hydroxide/pyridine in methanol, potassiumcyanide in ethanol and sodium hydroxide in aqueous alcohols, withpotassium hydroxide being preferred. The reaction is typically carriedout in an aqueous lower alcohol solvent,-such as methanol, ethanol,isopropyl alcohol, n-butanol, 2-ethoxyethanol or ethylene glycol orpyridine, at temperatures ranging from room temperature to the refluxtemperature of the solvent, and the reaction time varies from about ½hour to 100 hours.

[0542] In step g, the carboxy functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)may be amidated by techniques and procedures well known and appreciatedby one of ordinary skill in the art to give the correspondingω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (40).

[0543] In step h, the α-halo functionality of the appropriateω-halo-halocumylketone compound of structure (10) is carboxylated togive the corresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acidcompound of structure (46).

[0544] For example, a solution of the appropriate ω-halo-halocumylketonecompound of structure (10) and a suitable catalyst, such astetraethylammonium bromide, in a suitable polar aprotic organic solvent,such as acetonitrile, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone ordimethylformamide, are placed in a jacketed glass cell and fitted withan expanded silver mesh cathode, magnesium anode and carbon dioxidedelivery tube. Rotation of the electrodes provides stirring, whileelectrical contact with the electrodes is made via spring loaded slidingcarbon brushes placed against the concentric metal shafts (insulatedfrom each other with a length of plastic tubing) onto which theelectrodes are mounted. Carbon dioxide is introduced into the cell atpressures of 1-10 atm, for a period of time ranging from 30 minutes to50 hours and at a temperature range of from −30° C. to 50° C. Thecorresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound ofstructure (46) is isolated, after acidification with a suitable mineralacid, such as hydrochloric acid, by extractive methods as are known inthe art.

[0545] It is preferred that the ω-halo functionality of the appropriateω-halo-halocumylketone compound of structure (10) for use in step h be aω-chloro.

[0546] Alternatively, the treatment of appropriateω-halo-halocumylketone compound of structure (10) with a transitionmetal catalyst such as palladium, nickel or cobalt, optionally in thepresence of a phosphine catalysis using low to modest pressures ofcarbon monoxide as described by Stahly et al. in U.S. Pat. No.4,990,658, 1991 also provides the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure(46).

[0547] In step i, the appropriate the amide functionality of theappropriate ω′-halo-α′-keto-α,α-dimethylphenylacetic acid amide compoundof structure (40) is converted to the corresponding ester to give theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (31).

[0548] For example, the appropriateω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (40) is reacted with an appropriate hydrogen halide in anappropriate organic solvent such as ethanol. The reaction is typicallyconducted at a temperature range of from room temperature to reflux andfor a period of time ranging from 5 minutes to 1 hour. Theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (31) is recovered from the reaction zone by extractive methodsas is known in the art.

[0549] In step j, the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)wherein n=3 is ring-closed to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in Scheme A, step k.

[0550] In step k, the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)is ring-opened to give the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)wherein n=3 as described previously in Scheme A, step j.

[0551] In step 1, the nitrile functionality of the appropriatecyclopropyl cyanocumylketone compound of structure (20) is converted tothe corresponding ester by reaction with an appropriate C₁ to C₆ alcoholto give the cyclopropylketo-α,α-dimethylphenylacetic acid ester compoundof structure (32) as described previously in step a.

[0552] In step m, the nitrile functionality of the appropriatecyclopropyl cyanocumylketone compound of structure (20) is converted tothe corresponding amide to give theω′-halo-α′-keto-α,α-di-methylphenylacetic acid amide compound ofstructure (41) wherein R₆ and R₇ are both hydrogen as describedpreviously in step b.

[0553] In step n, the carboxy ester functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) is hydrolyzed to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step c.

[0554] In step o, the carboxy functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)may be esterified by techniques and procedures well known andappreciated by one of ordinary skill in the art to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid estercompound of structure (32) as described previously in step d.

[0555] In step p, the nitrile functionality of the appropriatecyclopropyl cyanocumylketone compound of structure (20) is converted tothe corresponding carboxy to give thecyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step e.

[0556] In step q, the amide functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) is converted to the corresponding acid by acid hydrolysisas is known in the art to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step f.

[0557] In addition, step q and step k may be combined and theω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)wherein n=3 may be prepared from the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) as described previously in Scheme A, step j.

[0558] In step r, the carboxy functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)may be amidated by techniques and procedures well known and appreciatedby one of ordinary skill in the art to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid amide compound ofstructure (41) as described previously in step g.

[0559] In step s, the α-halo functionality of the appropriatecyclopropyl halocumylketone compound of structure (11) is carboxylatedto give the corresponding cyclopropylketo-α,α-dimethylphenylacetic acidcompound of structure (47) as described previously in step h.

[0560] In step t, the appropriate the amide functionality of theappropriate cyclopropylketo-α,α-dimethylphenylacetic acid amide compoundof structure (41) is converted to the corresponding ester to give thecyclopropylketo-α,α-dimethylphenylacetic acid ester compound ofstructure (32) as described previously in step i.

[0561] In step u, the nitrile functionality of the appropriateω-halo-cyanoethylphenylketone compound of structure (21) is converted tothe corresponding ester by reaction with an appropriate C₁ to C₆ alcoholto give the ω′-halo-α′-keto-α-methylphenylacetic acid ester compound ofstructure (33) as described previously in step a.

[0562] In step v, the nitrile functionality of the appropriateω-halo-cyanoethylphenylketone compound of structure (21) is converted tothe corresponding amide to give the ω′-halo-α′-keto-α-methylphenylaceticacid amide compound of structure (42) wherein R₆ and R₇ are bothhydrogen as described previously in step b.

[0563] In step w, the carboxy ester functionality of the appropriateω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) is hydrolyzed to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid compound of structure (48) asdescribed previously-in step c.

[0564] In step x, the carboxy functionality of the appropriateω′-halo-α′-keto-α-methylphenylacetic acid compound of structure (48) maybe esterified by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) as described previously in step d.

[0565] Alternatively, step ee and step x may be combined and theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (33) wherein n=3 may be prepared from the correspondingcyclopropylketo-α-methylphenylacetic acid compound of structure (49) asdescribed previously in step d.

[0566] Alternatively, step jj, step ee and step x may be combined andthe ω-halo-α′-keto-a,-dimethylphenylacetic acid ester compound ofstructure (33) wherein n=3 may be prepared from the correspondingcyclopropyl cyanoethylphenylketone compound of structure (23) asdescribed previously in step d.

[0567] In step y, the nitrile functionality of the appropriateω-halo-cyanoethylphenylketone compound of structure (21) is converted tothe corresponding carboxy to give theω′-halo-α′-keto-α-methylphenylacetic acid compound of structure (48) asdescribed previously in step e.

[0568] In step z, the amide functionality of the appropriateω′-halo-α′-keto-α-methylphenylacetic acid amide compound of structure(42) is converted to the corresponding acid by acid hydrolysis as isknown in the art to give the ω′-halo-α′-keto-α-methylphenylacetic acidcompound of structure (48) as described previously in step f.

[0569] In step aa, the carboxy functionality of the appropriateω′-halo-α′-keto-α-methylphenylacetic acid compound of structure (48) maybe amidated by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the corresponding 107′-halo-α′-keto-α-methylphenylacetic abid amide compound of structure(42) as described previously in step g.

[0570] In step bb, the α-halo functionality of the appropriateω-halo-haloethylphenylketone compound of structure (12) is carboxylatedto give the corresponding ω′-halo-α′-keto-α-methylphenylacetic acidcompound of structure (48) as described previously in step h.

[0571] In step cc, the appropriate the amide functionality of theappropriate ω′-halo-α′-keto-α-methylphenylacetic acid amide compound ofstructure (42) is converted to the corresponding ester to give theω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) as described previously in step i.

[0572] In step dd, the appropriate ω′-halo-α′-keto-α-methylphenylaceticacid compound of structure (48) wherein n=3 is ring-closed to give thecorresponding cyclopropylketo-α-methylphenylacetic acid compound ofstructure (49) as described previously in Scheme A, step k.

[0573] In step ee, the appropriate cyclopropylketo-α-methylphenylaceticacid compound of structure (49) is ring-opened to give the correspondingω′-halo-α′-keto-α-methylphenylacetic acid compound of structure (48)wherein n=3 as described previously in Scheme A, step j.

[0574] In step ff, the nitrile functionality of the appropriatecyclopropyl cyanoethylphenylketone compound of structure (23) isconverted to the corresponding ester by reaction with an appropriate C₁to C₆ alcohol to give the cyclopropylketo-α-methylphenylacetic acidester compound of structure (35) as described previously in step a.

[0575] In step gg, the nitrile functionality of the appropriatecyclopropyl cyanoethylphenylketone compound of structure (23) isconverted to the corresponding amide to give thecyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) wherein R₆ and R₇ are both hydrogen as described previously in stepb.

[0576] In step hh, the carboxy ester functionality of the appropriatecyclopropylketo-α-methylphenylacetic acid ester compound of structure(35) is hydrolyzed to give the correspondingcyclopropylketo-α-methylphenylacetic acid compound of structure (49) asdescribed previously in step c.

[0577] In step ii, the carboxy functionality of the appropriatecyclopropylketo-α-methylphenylacetic acid compound of structure (49) maybe esterified by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingcyclopropylketo-α-methylphenylacetic acid ester compound of structure(35) as described previously in step d.

[0578] In step jj, the nitrile functionality of the appropriatecyclopropyl cyanoethylphenylketone compound of structure (23) isconverted to the corresponding carboxy to give thecyclopropylketo-α-methylphenylacetic acid compound of structure (49) asdescribed previously in step e.

[0579] In step kk, the amide functionality of the appropriatecyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) is converted to the corresponding acid by acid hydrolysis as isknown in the art to give the correspondingcyclopropylketo-α-methylphenylacetic acid compound of structure (49) asdescribed previously in step f.

[0580] In addition, step kk and step ee may be combined and theω′-halo-α′-keto-α-methylphenylacetic acid compound of structure (48)wherein n=3 may be prepared from the correspondingcyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) as described previously in Scheme A, step j.

[0581] In step 11, the carboxy functionality of the appropriatecyclopropylketo-α-methylphenylacetic acid compound of structure (49) maybe amidated by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingcyclopropylketo-α-methylphenylacetic acid amide compound of structure(44) as described previously in step g.

[0582] In step mm, the α-halo functionality of the appropriatecyclopropyl haloethylphenylketone compound of structure (14) iscarboxylated to give the correspondingcyclopropylketo-α-methylphenylacetic acid compound of structure (49) asdescribed previously in step h.

[0583] In step nn, the appropriate the amide functionality of theappropriate ω′-halo-α′-keto-α-methylphenylacetic acid amide compound ofstructure (42) is converted to the corresponding ester to give theω′-halo-α′-keto-α-methylphenylacetic acid ester compound of structure(33) as described previously in step i.

[0584] In step oo, the nitrile functionality of the appropriate ω-halocyanotolylketone compound of structure (22) is converted to thecorresponding ester by reaction with an appropriate C₁ to C₆ alcohol togive the ω′-halo-α′-keto-phenylacetic acid ester compound of structure(34) as described previously in step a.

[0585] In step pp, the nitrile functionality of the appropriate ω-halocyanotolylketone compound of structure (22) is converted to thecorresponding amide to give the ω′-halo-α′-keto-phenylacetic acid amidecompound of structure (43) wherein R₆ and R₇ are both hydrogen asdescribed previously in step b.

[0586] In step qq, the carboxy ester functionality of the appropriateω′-halo-α′-keto-phenylacetic acid ester compound of structure (34) ishydrolyzed to give the corresponding ω′-halo-α′-keto-methylphenylaceticacid compound of structure (50) as described previously in step c.

[0587] In step rr, the carboxy functionality of the appropriateω′-halo-α′-keto-methylphenylacetic acid compound of structure (50) maybe esterified by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingω′-halo-α′-keto-phenylacetic acid ester compound of structure (34) asdescribed previously in step d.

[0588] Alternatively, step yy and step rr may be combined and theω′-halo-α′-keto-phenylacetic acid ester compound of structure (34)wherein n=3 may be prepared from the correspondingω′-halo-α′-keto-methylphenylacetic acid compound of structure (50) asdescribed previously in step d.

[0589] Alternatively, step ddd, step yy and step rr may be combined theω′-halo-α′-keto-phenylacetic acid ester compound of structure (34)wherein n=3 may be prepared from the corresponding cyclopropylcyanotolylketone compound of structure (24) as described previously instep d.

[0590] In step ss, the nitrile functionality of the appropriate ω-halocyanotolylketone compound of structure (22) is converted to thecorresponding carboxy to give the ω′-halo-α′-keto-methylphenylaceticacid compound of structure (50) as described previously in step e.

[0591] In step tt, the amide functionality of the appropriateω′-halo-α′-keto-phenylacetic acid amide compound of structure (43) isconverted to the corresponding acid by acid hydrolysis as is known inthe art to give the ω′-halo-α′-keto-methylphenylacetic acid compound ofstructure (50) as described previously in step f.

[0592] In step uu, the carboxy functionality of the appropriateω′-halo-α′-keto-methylphenylacetic acid compound of structure (50) maybe amidated by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingω′-halo-α′-keto-phenylacetic acid amide compound of structure (43) asdescribed previously in step g.

[0593] In step vv, the α-halo functionality of the appropriate ω-halohalotolylketone compound of structure (13) is carboxylated to give thecorresponding ω′-halo-α′-keto-methylphenylacetic acid compound ofstructure (50) as described previously in step h.

[0594] In step ww, the appropriate the amide functionality of theappropriate ω′-halo-α′-keto-phenylacetic acid amide compound ofstructure (43) is converted to the corresponding ester to give theω′-halo-α′-keto-phenylacetic acid ester compound of structure (34) asdescribed previously in step i.

[0595] In step xx, the appropriate ω′-halo-α′-keto-methylphenylaceticacid compound of structure (50) wherein n=3 is ring-closed to give thecorresponding cyclopropylketo-phenylacetic acid compound of structure(51) as described previously in Scheme A, step k.

[0596] In step yy, the appropriate cyclopropylketo-phenylacetic acidcompound of structure (51) is ring-opened to give the correspondingω′-halo-α′-keto-methylphenylacetic acid compound of structure (50)wherein n=3 as described previously in Scheme A, step j.

[0597] In step zz, the nitrile functionality of the appropriatecyclopropyl cyanotolylketone compound of structure (24) is converted tothe corresponding ester by reaction with an appropriate C₁ to C₆ alcoholto give the cyclopropylketo-phenylacetic acid ester compound ofstructure (36) as described previously in step a.

[0598] In step aaa, the nitrile functionality of the appropriatecyclopropyl cyanotolylketone compound of structure (24) is converted tothe corresponding amide to give the cyclopropylketo-phenylacetic acidamide compound of structure (45) wherein R₆ and R₇ are both hydrogen asdescribed previously in step b.

[0599] In step bbb, the carboxy ester functionality of the appropriatecyclopropylketo-phenylacetic acid ester compound of structure (36) ishydrolyzed to give the corresponding cyclopropylketo-phenylacetic acidcompound of structure (51) as described previously in step c.

[0600] In step ccc, the carboxy functionality of the appropriatecyclopropylketo-phenylacetic acid compound of structure (51) may beesterified by techniques and procedures well known and appreciated byone of ordinary skill in the art to give the correspondingcyclopropylketo-phenylacetic acid ester compound of structure (36) asdescribed previously in step d.

[0601] In step ddd, the nitrile functionality of the appropriatecyclopropyl cyanotolylketone compound of structure (24) is converted tothe corresponding carboxy to give the cyclopropylketo-phenylacetic acidcompound of structure (51) as described previously in step e.

[0602] In step eee, the amide functionality of the appropriatecyclopropylketo-phenylacetic acid amide compound of structure (45) isconverted to the corresponding acid by acid hydrolysis as is known inthe art to give the corresponding cyclopropylketo-phenylacetic acidcompound of structure (51) as described previously in step f.

[0603] In addition, step yy and step eee may be combined and theω′-halo-α′-keto-methylphenylacetic acid compound of structure (50)wherein n=3 may be prepared from the correspondingcyclopropylketo-phenylacetic acid amide compound of structure (45) asdescribed previously in Scheme A, step j.

[0604] In step fff, the carboxy functionality of the appropriatecyclopropylketo-phenylacetic acid compound of structure (51) may beamidated by techniques and procedures well known and appreciated by oneof ordinary skill in the art to give the correspondingcyclopropylketo-phenylacetic acid amide compound of structure (45) asdescribed previously in step g.

[0605] In step ggg, the α-halo functionality of the appropriatecyclopropyl halotolylketone of structure (15) is carboxylated to givethe corresponding cyclopropylketo-phenylacetic acid compound ofstructure (51) as described previously in step h.

[0606] In step hhh, the appropriate the amide functionality of theappropriate cyclopropylketo-phenylacetic acid amide compound ofstructure (45) is converted to the corresponding ester to give thecyclopropylketo-phenylacetic acid ester compound of structure (36) asdescribed previously in step i.

[0607] Starting materials for use in Scheme H are readily available toone of ordinary skill in the art.

[0608] The following examples present typical syntheses as described inScheme H. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 26 Step a: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionicacid, methyl ester

[0609] Place anhydrous methanol (5 mL) under argon, cool to 0° C. andadd hydrogen chloride until saturated. Add2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionitrile (103 mg, 4.12mmol), remove the ice bath and stir for 5 hours at room temperature.Allow to stand at −10° C. overnight, and stir an additional 3 hours atroom temperature. Pour into cracked ice (20 g) and allow to stand for 5minutes. Evaporate the solvent in vacuo to ½ volume, dilute with waterand extract with methylene chloride (3X). Combine the organic layers,wash with saturated sodium hydrogen carbonate and brine. Dry (MgSO₄),filter and evaporate the solvent in vacuo. Extract the residue into hothexane (12 mL), filter hot and evaporate the solvent in vacuo to givethe title compound as a colorless oil (97 mg, 83%).

EXAMPLE 27 Step d: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionicacid, ethyl ester

[0610] Add anhydrous hydrogen chloride gas (18.0 g) to anhydrous ethanolDB (210 g) by purging the solution. Add this hot solution (60° C. ) to asolution of 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (31g, 115.6 mmol) and reflux under a nitrogen atmosphere for 2.5 hours.Evaporate the solvent in vacuo, dissolve the residue in methylenechloride (150 mL) and wash with water (2×100 mL). Dry (MgSO₄), filterthrough silica gel, washing the gel with methylene chloride (250 mL).Combine the organic washings and evaporate the solvent in vacuo to givethe title compound as a colorless oil (33.3 g, 97%).

[0611]¹H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.3Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.70 (t, J=6.6 Hz, 2H), 3.19 (t, J=6.8Hz, 2H), 2.25 (p, J=6.6 Hz, 2H), 1.61 (s, 6H), 1.20 (q, J=7.1 Hz, 3H);13 C. NMR (75 MHz, CDCl₃) δ 198.4, 176.0, 150.3, 135.1, 128.1, 126.0,61.0, 46.8, 44.6, 35.2, 26.7, 26.3, 14.0; IR (neat) 2978, 1728, 1686,1606, 1254, 1231, 1148, 1097 cm⁻¹.

[0612] Anal. Calcd for C₁₆H₂₁O₃ Cl: C, 64.75; H, 7.13; Found: C, 64.24;H, 7.18.

EXAMPLE 28 Step d: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionicacid, methyl ester

[0613] Dissolve 2-[4-(⁴-chloro-butyryl)-phenyl]-2-methyl-propionic acid(6.2 g, 23.1 mmol) in hot methanolic solution of anhydrous hydrogenchloride (42 mL of a methanol containing 3.2 g of anhydrous hydrogenchloride). Reflux for 42 minutes, evaporate the solvent in vacuo,dissolve the residue in methylene chloride and wash with water. Dry(MgSO₄), filter through silica gel, washing the gel with methylenechloride. Combine the organic washings and evaporate the solvent invacuo to give the title compound as a clear oil (6.21 g, 94%).

[0614]¹H NMR (30 MHz, CDCl₃) δ 7.95 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5Hz, 2H), 3.66 (s, 3H), 3.67 (t, J=6.6 Hz, 2H), 3.17 (t, J=6.6 Hz, 2H),2.30 (p, J=6.6 Hz, 2H), 1.61 (s, 6H); 13 C. NMR (75 MHz, CDCl₃) δ 198.0,176.2, 149,8, 135.0, 128.0, 125.8, 52.4, 46.9, 44.7, 35.3, 26.8, 26.5.

[0615] Anal. Calcd for C₁₅Hl₉O₃ Cl: C, 63.72; H, 6.77; Found: C, 63.50;H, 6.67.

EXAMPLE 29 Step d: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionicacid, methyl ester

[0616] Mix 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (10.0g, 37.3 mmol) and anhydrous potassium carbonate (3.5 g, 25.3 mmol). Heatto 40° C. in acetonitrile (100 mL) and stir under a nitrogen atmosphere.Add dimethyl sulfate (13.3 g, 105 mmol) and reflux for 45 minutes.Evaporate the solvent in vacuo, dissolve the residue in ethyl acetate(50 mL) and wash with water (4×50 mL). Dry (MgSO₄), filter throughsilica gel and evaporate the solvent in vacuo to give the title compound(6.4 g, 89%).

EXAMPLE 30 Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionicacid

[0617] Fit a jacketed glass cell of about 6 L capacity with a rotatingexpanded silver mesh cathode/magnesium anode assembly, a carbon dioxidedelivery tube, and a stainless steel thermocouple. Load the cell withacetonitrile (5.8 L) and tetraethylammonium bromide (26 g). Sparge withcarbon dioxide and cool in cooling bath. When the contents of the cellreach −10° C., add hydrogen chloride remediated1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one and1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (424.9 g,53.5 mole % bromo and 20.4 mole % chloro by HPLC analysis, 1087 mmoltotal active tertiary benzylic halide) and perform electrolysis at acontrolled current of 8 amps (20 mA cm⁻²) for 6 hours. Drain thecontents, acidify with chilled aqueous 6M hydrochloric acid, extract,evaporate the solvent in vacuo and recrystallize to give the titlecompound (186 g, 64%); 78.5-80.3° C.

[0618] 1H NMR (300 MHz, CDCl₃) δ 10.5 (br s, 2H), 7.96 (d, J=8.2 Hz,2H), 7.50 (d, J=8.2 Hz, 2H), 3.67 (t, J=6.8 Hz, 2H), 3.17 (t, J=6.8 Hz,2H), 2.22 (m, J=6.7 Hz, 2H), 1.63 (s, 6H); 13 C. NMR (75 MHz, CDCl₃) δ198.2, 181.9, 149.0, 135.2, 128.1, 126.1, 46.7, 44.7, 35.3,- 26.9, 26.7;MS (CIMS (Methane)) 271 (3), 269 (11), 233 (100), 187 (75).

[0619] Anal. Calcd for C₁₄H₁₇O₃ Cl: C, 62.57; H, 6.38; Found: C, 63.10;H, 6.59.

EXAMPLE 31 Step h: 2-[(4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionicacid

[0620] Fit a jacketed glass cell of about 50 mL capacity with anexpanded silver mesh cathode (14 cm² geometric area), a roughlyconcentric magnesium sacrificial anode, a tube to deliver carbon dioxidegas and a magnetic stir bar. Add a solution of hydrogen chlorideremediated 1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-oneand 1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.79 g,89 mole %, 3:1 ratio of tertiary benzylic bromide to tertiary benzylicchloride by NMR, approximately 8.6 mmol total active tertiary benzylichalide) in acetonitrile (45 mL) and tetraethylammonium bromide (0.19 g).Close the cell and cool to −10° C. with a continuous carbon dioxidesparge for 169 minutes at an average current density of 13 mA cm⁻². Warmto contents of the cell to ambient temperature, drain the contents,acidify with chilled aqueous 6M hydrochloric acid, extract and evaporatethe solvent in vacuo to give the title compound (1.53 g, 66%).

EXAMPLE 32 Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionicacid

[0621] Fit a jacketed glass cell of 50 mL capacity with an expandedsilver mesh cathode (14 cm2 geometric area), a roughly concentricmagnesium sacrificial anode, a tube to deliver carbon dioxide gas, and amagnetic stir bar. Cool the cell to −10° C. under carbon dioxide. Add asolution of tetraethylammonium chloride (40 mL of a 0.02M solution indimethylformamide) and1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.91 g, 85%pure by NMR, 9.81 mmol) and carry out electrolysis for 178 minutes at anaverage current density of 12.4 mA cm-2: the total charge passed isequal to 98% of the calculated theoretical two electron value. Warm thecontents of the cell to ambient temperature, drain the contents, acidifywith chilled aqueous 6M hydrochloric acid, extract and evaporate thesolvent in vacuo to give the title compound (1.89 g, 72%).

EXAMPLE 33 Step m:2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionamide

[0622] Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile(100 mg) in aqueous ethanolic potassium hydroxide (2 mL) (prepared fromethanol (5 mL), water (5 mL) and solid potassium hydroxide (1.5 g). Stirovernight at room temperature, then heat at reflux for 6 hours. Cool andevaporate the solvent in vacuo to give the title compound.

EXAMPLE 34 Step t: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionicacid, ethyl ester

[0623] Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionamide(100 mg) in ethanol and bubble in hydrochloride gas for 5 minutes whilestirring. Reflux for 10 hours, distill off the ethanol and extract intoethyl acetate. Evaporate the solvent in vacuo to give the title compoundas an oil (50 mg).

EXAMPLE 35 Step k and step q:2-[4-(4-Bromo-butyryl)-phenyl]-2-methyl-propionic acid

[0624] Treat2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-N-methyl-N-methoxy-propionamide(0.15 g, 0.53 mmol) with 48% HBr (1 mL) for 2 hours at 80° C. Cool toroom temperature, dilute with water (5 mL) and neutralize with aqueoussodium hydrogen carbonate until pH 7. Extract with methylene chloride(3×15 mL), dry (Na₂SO₄), filter and evaporate the solvent in vacuo.Purify by silica gel chromatography (3:1 hexane/ethyl acetate) to givethe title compound (0.15 g, 95%).

[0625]¹H NMR (CDCl₃) δ 7.97 (d, 2H), 7.51 (d, 2H), 3.53 (t, 2H), 3.16(t, 2H), 2.30 (quin, 2H), 1.60 (s, 6H); 13 C. NMR (CDCl₃) δ 198.4,181.8, 149.5, 131.0, 128.3, 126.3, 46.6, 36.5, 33.6, 26.9, 26.1; MS (CI)(M⁺+H) 303 (100), 315 (98), 233 (80).

EXAMPLE 36 Step p: 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionicacid

[0626] Combine 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile(0.5 g) in 12.5% sodium hydroxide (20 mL) and ethanol (12.5 mL). Heat toreflux for 21 hours, cool and remove the ethanol by vacuum distillation.Extract the residual aqueous suspension with methylene chloride (40 mL),acidify the aqueous phase with 20% HCl and extract with methylenechloride (2×40 mL). Combine the organic phases, dry (Na2SO₄) andevaporate the solvent in vacuo to give the title compound as acrystalline solid (350 mg, 70%); mp 83-85° C.

[0627]¹H NMR (CDCl₃) δ 7.50-8.00 (4H, d), 2.66 (1H, m), 1.62 (6H, s),1.24 (2H, m), 1.04 (2H, m).

[0628] The following compounds can be prepared by using the proceduresdepicted in Scheme H:

[0629] (4-Cyclopropanecarbonyl-phenyl)-acetic acid;

[0630] 2-(4-Cyclopropanecarbonyl-phenyl)-propionic acid;

[0631] 2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid;

[0632] [4-(4-Chloro-butyryl)-phenyl]-acetic acid;

[0633] 2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid;

[0634] 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid;

[0635] (4-Cyclopropanecarbonyl-phenyl)-acetic acid, ethyl ester;

[0636] 2-(4-Cyclopropanecarbonyl-phenyl)-propionic acid, ethyl ester;

[0637] [4-(4-Chloro-butyryl)-phenyl]-acetic acid, ethyl ester;

[0638] 2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, ethyl ester;

[0639] 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, ethylester;

[0640] (4-Cyclopropanecarbonyl-phenyl)-acetamide;

[0641] 2-(4-Cyclopropanecarbonyl-phenyl)-propionamide;

[0642] [4-(4-Chloro-butyryl)-phenyl]-acetamide;

[0643] 2-[4-(4-Chloro-butyryl)-phenyl]-propionamide; and

[0644] 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionamide.

[0645] In addition, the novel intermediate of formula (II) wherein R₅ isCOOH may be prepared as described in Scheme I. In Scheme I, allsubstituents are as previously defined unless otherwise indicated.

[0646] D′═—C(═O)CH₃ or —C(═O)C₆H₅

[0647] Scheme I provides a general synthetic procedure for preparing thenovel intermediate of formula (II) wherein R₅ is COOH.

[0648] In step a, the neophyl acetate of benzoate of structure (53) isacylated with an appropriate ω-halo compound of the structureHal—(CH₂)_(n)—C(═O)—B, wherein B is Hal or hydroxy, Hal is Cl, Br or Iand n is as previously defined to give the correspondingω′-halo-α′-keto-(2-methylpropanol)benzene acetate or benzoate compoundof structure (54) as described previously in Scheme A, step d.

[0649] The neophyl acetate of benzoate of structure (53) is prepared byreacting a methallyl halide of structure

[0650] wherein Hal is Cl, Br or I with sodium acetate or sodium benzoatein a suitable organic solvent such as 1-methyl-2-pyrrolidinone. Thereactants are heated at a temperature of approximately 100 to 130° C.and the corresponding to give the methallyl acetate or benzoate ofstructure

[0651] wherein D′ is —C(═O)CH₃ or —C(═O)C₆H₅ which is collected bydistillation.

[0652] A benzene compound of structure

[0653] wherein A is defined above is then alkylated with the methylallylacetate or benzoate of structure

[0654] wherein D′ is —C(═O)CH₃ or —C(═O)C₆H₅ to give the neophyl acetateor benzoate of structure (53) as described previously in Scheme A, stepd.

[0655] In step a₂, the neophyl acetate or benzoate of structure (53) isacylated with an appropriate cyclopropyl compound of the structure

[0656] wherein B is as previously defined to give the correspondingcyclopropyl neophyl acetate or benzoate of structure (55) as describedpreviously in Scheme A, step e.

[0657] In step b₁, the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene acetate or benzoate compoundof structure (54) wherein n=3 is ring-closed to give the correspondingcyclopropyl neophyl acetate or benzoate of structure (55) as describedpreviously in Scheme A, step k.

[0658] In step b₂, the appropriate cyclopropyl neophyl acetate orbenzoate of structure (55) is ring-opened to give the correspondingω′-halo-α′-keto-(2-methylpropanol)benzene acetate or benzoate compoundof structure (54) wherein n=3 as described previously in Scheme H, stepj.

[0659] In step c₁, the acetate or benzoate functionality of theappropriate ω′-halo-α′-keto-(2-methylpropanol)benzene acetate orbenzoate compound of structure (54) is hydrolyzed with concentratedhydrochloric acid in ethanol at reflux temperature for a period of timeranging from 1-10 hours. The correspondingω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (56) isrecovered from the reaction zone by extractive methods as is known inthe art.

[0660] In step c₂, the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene acetate or benzoate compoundof structure (54) wherein n=3 is ring closed and the acetate or benzoatefunctionality hydrolyzed with base to give the cyclopropyl neophylalcohol compound of structure (57).

[0661] For example, the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene acetate or benzoate compoundof structure (54) wherein n=3 is reacted with 40% aqeuoustetrabutylammonium hydroxide and 50% aqeuous sodium hydroxide at refluxtemperature for a period of time ranging from 5-72 hours. Thecyclopropyl neophyl alcohol compound of structure (57) may be recoveredfrom the reaction zone by extractive methods as are known in the art.

[0662] In step C_(3,) the acetate or benzoate functionality of theappropriate cyclopropyl neophyl acetate or benzoate of structure (55) ishydrolyzed to give the corresponding cyclopropyl neophyl alcohol ofstructure (57).

[0663] For example, the appropriate cyclopropyl neophyl acetate orbenzoate of structure (55) is reacted with 50% aqueous sodium hydroxideat reflux temperature for a period of time ranging from 5 minutes to 5hours. The corresponding cyclopropyl neophyl alcohol of structure (57)is recovered from the reaction zone by extractive methods as are knownin the art.

[0664] In step d₁, the ω′-halo-α′-keto-(2-methylpropanol)benzene acetateor benzoate compound of structure (54) is converted to the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure(46).

[0665] For example, the appropriate cyclopropyl neophyl alcohol ofstructure (54) may be reacted with ruthenium chloride/sodium periodatein a suitable organic solvent such as acetonitrile and/or carbontetrachloride, ruthenium chloride/sodium hypochloride in a suitablesolvent such as acetic acid/water, potassium permanganate in a suitablesolvent such as acetic acid/water, fumic nitric acid in acetic acid orsodium nitrite/concentrated nitric acid in acetic acid. The reactantsare typically mixed stirred together at a temperature range of 10° C. to50° C. and for a period of time ranging from 30 minutes to 10 hours. Thecorresponding cyclopropylketo-α,α-dimethylphenylacetic acid compound ofstructure (46) is recovered from the reaction zone by extractive methodsas is known in the art.

[0666] In step d₂, the ω′-halo-α′-keto-(2-methylpropanol)benzenecompound of structure (56) is converted to the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure(46).

[0667] For example, the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (56) maybe oxidized with potassium permanganate in suitable acid solvent such asacetic acid. The reactants are typically reacted at a temperature rangeof from about 0° C. to 5° C. for a period of time ranging from 30minutes to 10 hours. The correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)is recovered from the reaction zone by extractive methods as are knownin the art and may be purified by recrystallization. Other oxidizingreagents suitable for the oxidation of the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (56) tothe corresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acid compoundof structure (46) are nitric acid, chromium (IV) oxide, nitrogendioxide, ruthenium (VIII) oxide, nickel peroxide, silver oxide, t-butylchromate, xenic acid

[0668] In step d₃, the hydroxymethyl functionality of the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (56) isoxidized with a variety of oxidizing agents and methods to give thecorresponding ω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound ofstructure (58).

[0669] One such method involves a procedure in which the hydroymethylfunctionality of the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (56) isoxidized to the corresponding aldehyde functionality using, for example,Swern Oxidation conditions (dimethyl sulfoxide, oxalyl- chloride andtriethylamine), as is known in the art. The Swern Oxidation is carriedout in a suitable aprotic organic solvent such as methylene chloride attemperatures ranging from about −78° C. to room temperature, and thereaction time vaires from about ½ hours to 8 hours. Other suitablereagents for the oxidation of the hydroxyethyl functionality of theappropriate ω′-halo-α′-keto-(2-methylpropanol)benzene compound ofstructure (56) to the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) are Dess-Martin reagent, chromium (IV) oxide, nickel peroxide,sodium dichromate, potassium dichromate, t-butyl chromate, silver oxide,argentic picolinate, manganese dioxide, lead tetraacetate,dicyclohexylcarbodiimide, 2,3-dichloro-5,6-dicyanoquinone,tetrachloro-1,2-benzoquinone, 2,2,6,6-tetramethylpiperidinyl-1-oxy(TEMPO) or quinolinium chlorochromate.

[0670] In step d₄, the hydroxymethyl functionality of the appropriatecyclopropyl neophyl alcohol of structure (57) is oxidized to give thecorresponding cyclopropylketo-α,α-dimethylphenylacetaldehyde compound ofstructure (59) as described previously in step d₃.

[0671] In step d₅, the appropriate cyclopropyl neophyl alcohol ofstructure (57) is converted to the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step d₂.

[0672] In step d₆, the appropriate cyclopropyl neophyl acetate orbenzoate of structure (55) is converted to the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step d₁.

[0673] In step e₁, the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (56)wherein n=3 is ring-closed to give the corresponding cyclopropyl neophylalcohol of structure (57) as described previously in Scheme H, step j.

[0674] In step e₂, the appropriate cyclopropyl neophyl alcohol ofstructure (57) is ring-opened to give the correspondingω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (56)wherein n=3 as described previously in Scheme H, step k.

[0675] In step f₁, the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) wherein n=3 is ring-closed to give the correspondingcyclopropylketo-α,α-dimethylphenylacetaldehyde compound of structure(59) as described previously in Scheme H, step j.

[0676] In step f₂, the appropriatecyclopropylketo-α,α-dimethylphenylacetaldehyde compound of structure(59) is ring-opened to give the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) wherein n=3 as described previously in Scheme H, step k.

[0677] In step g₁, the aldehyde functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) is oxidized to give the correspondingω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure(46).

[0678] For example, the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) is reacted with, for example, potassium permanganate. The potassiumpermanganate oxidation is scarried out in a suitable acidic medium suchas hydrochloric acid/acetone at a temperature ranging from about 0° C.to room temperature and the reaction time varies from about ½ hour to 8hours. Other suitable reageants for the oxidation of theω′-halo-α′-keto-α,α-dimethylphenylacetaldehyde compound of structure(58) to the corresponding ω′-halo-α′-keto-α,α-dimethylphenylacetic acidcompound of structure (46) are chromium (IV) oxide, silver (I) oxide,silver oxide, argentic picolinate, peroxide, nitric acid,m-chloroperbenzoic acid and peracetic acid.

[0679] In step g₂, the aldehyde functionality of the appropriatecyclopropylketo-α,α-dimethylphenylacetaldehyde compound of structure(59) is oxidized to give the correspondingcyclopropylketo-α,α-dimethylphenylacetic acid compound of structure (47)as described previously in step

[0680] Starting materials for use in Scheme I are readily available toone of ordinary skill in the art.

[0681] The following examples present typical syntheses as described inScheme I. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 37 Step a₁: 2-(4-(4-Chloro-1-oxo-butyl))-phenyl-2-methylpropanyl acetate

[0682] Mix 1-methyl-2-pyrrolidinone (400 mL, sodium acetate (205 g, 2.5mol), stir at heat to 100° C. in a reaction flask which is fitted with adistillation head. Add, by dropwise addition, methylallyl chloride (181g, 2.0 mol) over 1 hour. Heat the pot to 120° C. for 30 minutes collectmethallyl acetate by distillation (193 g).

[0683] Mix methallyl acetate (228 g, 2.0 mol) and benzene (1 L) and coolto 5° C. Add aluminum chloride (266 g, 2.0 mol) over approximately 30minutes while maintaining the temperature below 10° C. Add, in portionsof 50 mL to 80 mL each, to a 5° C. mixture of aluminum chloride (15 g)in benzene (600 mL). After addition is complete, stir at 0-3° C. for ½hour, pour onto ice (2 kg) and separate the organic layer. Wash withwater (2×300 mL), dry (Na₂SO₄), and distill to give neophyl acetate.

[0684] Dissolve neophyl acetate (150 g, 0.78 mol) in methylene chloride(390 mL) and cool to 5° C. Add anhydrous aluminum chloride (104 g, 0.78mol) at such a rate that the temperature is maintained below 10° C. Coolthe reaction mixture to 5° C. Dissolve anhydrous aluminum chloride (122g) in methylene chloride (390 mL) and cool to 5° C. Add 4-chlorobutyrylchloride (132 g, 0.94 mol) at such a rate that the temperature is keptbelow 10° C. Cool the reaction to 5° C. and add the neophylacetate-aluminum chloride solution in one portion and stir between −5°C. and 5° C. for 19 hours. Pour slowly over crushed ice (1.5kg),separate the organic phase and wash with water (3×300 mL), cold aqueouspotassium carbonate (10%, 300 mL) and water (300 mL). Evaporate thesolvent in vacuo and filter to give the title compound as a light-brownoil (221.1 g, 95.6%).

[0685]¹H NMR (300 MHz, CDCl₃) δ 1.34 (6H, s), 1.95 (3H, s), 2.18 (2H,quent.), 3.13 (2H, t), 3.65 (2H, t), 4.12 (2H, s), 7.43, 7.90 (2H each,d).

EXAMPLE 38 Step b₁: 2-(4-(1-Oxo-1-cyclopropanyl)-phenyl-2-methylpropanylacetate

[0686] Mix 2-(4-(4-chloro-1-oxo-butyl))-phenyl-2-methyl propanyl acetate(37.0 g, 0.125 mol), tetrabutylammonium hydroxide (8.1 g of a 40%aqueous solution), methylene chloride (300 mL) and 50% sodium hydroxide(40 mL). Stir vigorously at room temperature for 4 hours, add water (100mL) and separate the organic layer. Wash with water (2×100 mL), dry(MgSO₄) and evaporate the solvent in vacuo to give the title compound(29.9 g).

[0687]¹H NMR (300 MHz, CDCl₃) δ 1.00, 1.19 (2H each, m), 1.34 (6H, s),1.95 (3H, s), 2.65 (1H, m), 4.13 (2H, s), 7.44, 7.95 (2H each, d).

EXAMPLE 39 Step c₁: 2-(4-(4-Chloro-1-oxobutyl)-phenyl-2-methylpropanol

[0688] Mix 2-(4-(4-chloro-1-oxo-butyl))-phenyl-2-methyl propanylacetate, concentrated hydrochloric acid (555 mL), and ethanol (2.5 L)and reflux for 2.5 hours under a nitrogen atmosphere. Evaporate thesolvent in vacuo and take the residue up in methylene chloride (1 L).Wash sequentially with water (2×400 mL), aqueous potassium carbonate(10%, 200 mL) and water (300 mL). Evaporate the solvent in vacuo to givethe title compound as a light-brown oil (200 g, 90%).

[0689]¹H NMR (300 MHz, CDCl₃) δ 1.35 (6H, s), 2.21 (2H, quent.) 3.15,(2H, t), 3.64 (2H, s), 3.66 (2H, 5), 7.48, 7.93 (2H each, d).

EXAMPLE 40 Step c₂:2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropanol

[0690] Mix 2-(4-(4-chloro-1-oxobutyl)-phenyl-2-methylpropanol (101 g,0.34 mol), methylene chloride (800 mL), 40% aqueous solution oftetrabutylammonium hydroxide (33 g), and 50% aqueous solution of sodiumhydroxide (162 mL) and reflux for 48 hours. Add water (300 mL), separatethe organic phase and wash with water (2×300 mL). Dry (MgSO₄) andevaporate the solvent in vacuo to give the title compound as alight-brown oil (71.1 g, 96%).

EXAMPLE 41 Step c₁:2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropanol

[0691] Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanyl acetate(4.16 g, 14 mmol), ethanol (50 mL) and water (5 mL). Add 50% aqeuoussodium hydroxide (4.48 mL, 56 mmol). Stir and heat at reflux for 30minutes then remove the ethanol in vacuo. Extract the aqueous residuewith methylene chloride (2×25 mL), wash with water (2×25 mL), dry(MgSO₄) and evaporate the solvent in vacuo to give the title compound asa brown oil (2.91 g, 95.3%).

[0692]¹H NMR (300 MHz, CDCl₃) δ 1.03, 1.20 (2H each, m), 1.35 (6H, s),1.70 (1H, t, br), 2.66 (1H, m), 3.64 (2H, d), 7.48, 7.98 (2H each, d).

EXAMPLE 42 Step d₂:2-(4-(4-Chloro-2-oxo-butyl))-phenyl-2-methylpropionic acid

[0693] Mix powdered potassium permanganate (39.5 g, 0.25 mol), water (34mL) and acetic acid (200 mL). Stir and cool at 0° C., then add 85%phosphoric acid (4.2 g). Stir vigorously and add2-(4-(4-chloro-1-oxo-butyl))-phenyl-2-methylpropanol (24.5 g, 0.1 mol)in acetic acid (50 mL) at such a rate as to keep the temperature below5° C. Stir for 5.5 hours below 5° C., add ice water (300 mL), thensodium metabisulfite (45 g) in small portions until the dark brownmixture becomes colorless. Extract the aqueous solution with methylenechloride (3×150 mL), wash with water (100 mL) then extract with 20%aqueous potassium carbonate (2×150 mL). Wash the aqeuous phase withmethylene chloride (50 mL), cool in an ice-bath and acidify carefullywith concentrated hydrochloric acid until pH 3. Extract with methylenechloride (2×150 mL), wash wih water (2×80 mL) and dry (MgSO₄). Evaporatethe solvent in vacuo to give the title compound as a crystalline solid(21.25 g).

[0694]¹H NMR (300 MHz, CDCl₃) δ 1.63 (6H, s), 2.22 (2H, quent.), 3.17(2H, t), 3.67 (2H, t), 7.50, 7.92 (2H each, d), 12.3 (1H, s, br).

EXAMPLE 43 Step d₅:2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropionic acid

[0695] Method A:

[0696] Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (1.46g, 6.7 mmol), ruthenium chloride (0.036 g, 0.17 mmol), acetonitrile (14mL), carbon tetrachloride (14 mL) and water (20 mL). Stir vigorously andadd sodium periodate (5.85 g) in one portion. Stir at room temperaturefor one hour longer, partition between methylene chloride (20 mL) andwater (5 mL), separate the organic layer, extract the aqeuous layer withmethylene chloride (15 mL) and wash the combined methylene chloridelayers with water (15 mL) and extract with 20% aqueous potassiumcarbonate (2×25 mL). Cool the base solution in an ice-bath, acidifycarefully with concentrated hydrochloride acid to pH 3 and extract intomethylene chloride (2×30 mL). Wash with water (15 mL), dry (MgSO₄) andevaporate the solvent in vacuo to give the title compound as a yellowoil (1.41 g, 90%).

[0697] 1H NMR (300 MHz, CDCl₃) δ 1.04, 1.23 (2H each, d), 1.63 (6H, s),2.65 (1H, m), 7.50, 7.99 (2H each, d).

[0698] Method B:

[0699] Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (10.9g, 50 mmol), ruthenium chloride (0.032 g, 0.16 mmol), acetic acid (100ml) and water (25 mL). Cool to 10° C. and add, by dropwise addition, anaqueous solution of sodium hypochloride (70 ml), stirring vigorouslyover a 30-minute period. Stir below 10° C. for 30 minutes longer,evaporate most of the solvent in vacuo and take the residue up inmethylene chloride (120 mL). Wash the methylene chloride solution withwater (2×40 mL) and extract with 20% aqueous potassium carbonate (2×50mL). Cool the base solution in an ice-bath, acidify carefully withconcentrated hydrochloride acid to ph 3 and extract into methylenechloride (2×50 mL). Wash the organic layer with water (40 mL), dry(MgSO₄) and evaporate the solvent in vacuo to give the title compound asa light-yellow oil (5.46 g, 47%).

[0700] Method C:

[0701] Mix potassium permanganate (3.61 g, 22.8 mmol), water (2 mL) andacetic acid (10 mL). Stir and cool to 10° C. and add 85% phosphoric acid(500 mg). Add, by dropwise addition, a solution2-(4-(1-oxo-1--cyclopropanyl))-phenyl-2-methylpropanol (1.66 g, 7.6mmol) in acetic acid (5 mL) over 5 minutes. Stir below 10° C. for 1 hourand then at room temperature for 5 hours. Add water (20 mL) followed byaddition of Na₂S₂O₅ in small portions until the solution becomescolorless. Extract with methylene chloride (2×50 mL), wash the methylenechloride solution with water (30 mL) and then extract with 10% aqueouspotassium carbonate (2×50 mL). Cool the base solution in an ice-bath,acidify carefully with concentracted hydrochloric acid to pH 3 andextract with methylene chloride (2×50 mL). Wash the organic layer withwater (20 mL), dry (MgSO₄) and evaporate the solvent in vacuo to givethe title compound as a colorless needles (1.20 g, 68%). ¹H NMR (300MHz, CDCl₃) δ 1.00 (4H, d), 1.50 (6H, s), 7.49, 8.00 (2H each, d), 12.6(1H, s, br).

[0702] Method D:

[0703] Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (2.30g, 10.6 mmol), acetic acid (5.5 mL) and fuming nitric acid (6.5 mL).Stir and heat at 48-50° C. for 2 hours, cool and add ice water (20 mL)followed by methylene chloride (60 mL). Separate the organic layer, washwith water (2×20 mL) and extract into 10% aqueous potassium carbonate(2×40 mL). Wash the alkaline solution with methylene chloride (10 mL)and cool in an ice-bath. Acidify carefully with concentratedhydrochloric acid to ph 3, extract with methylene chloride (2×40 mL),wash the combined organic layers with water (20 mL), dry (MgSO₄) andevaporate the solvent in vacuo to give the title compound aslight-yellow needles (1.89 g, 77%).

[0704] Method E:

[0705] Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanol (2.26g, 10.4 mmol), sodium nitrite (60 mg), acetic acid (5 mL) andconcentrated nitric acid (6 mL, d=1.42, 70%, 94 mmol). Stir and heat at48-50° C. for 2 hours, cool and dilute with ice water (20 mL). Extractinto methylene chloride (2×30 mL), wash the combined organic layers withwater (2×20 mL) and extract into 10% aqeuous potassium carbonate (2×40mL). Wash the alkaline solution with methylene chloride (10 mL) and coolin an ice-bath. Acidify carefully with concentrated hydrochloric acid topH 3 and extract into methylene chloride (2×40 mL). Wash the combinedorganic layers with water (20 mL), dry (MgSO₄) and evaporate the solventin vacuo to give the title compound as light yellow needels (2.01 g,83%).

EXAMPLE 44 Step d₆:2-(4-(1-Oxo-1-cyclopropanyl))-phenyl-2-methylpropionic acid

[0706] Mix 2-(4-(1-oxo-1-cyclopropanyl))-phenyl-2-methylpropanyl acetate(5.0 g, 0.0197 mol), sodium nitrite (100 mg), acetic acid (10 mL) andconcentrated nitric acid (8.7 mL, d=1.42, 70%, 0.137 mol). Stir and heatat 48-50° C. for 5.5 hours, cool and dilute with ice water (40 mL).Extract into methylene chloride (2×70 mL), wash the combined methylenechloride extracts with water (2×50 mL) and reduce the volue to 50 mL invacuo. Extract with 10% aqueous potassium carbonate (2×50 mL), was thebase solution with methylene chloride (20 mL) and cool in an ice-bath.Acidify carefully with concentrated hydrochloric acid to pH 3 andextract into methylene chloride (2×60 mL). Wash the combined methylenechloride extracts with water (30 ml), dry (MgSO₄) and evaporate thesolvent in vacuo to give the title compound asa crystalline solid (4.12g, 90%).

[0707] The novel intermediates of formula (X) wherein R₅ is H, Br, Cl,I, CN, —COOH, —COOalkyl or —CONR₆R₇ may be prepared as described inScheme J. In Scheme J, all substituents are as previously defined unlessotherwise indicated.

[0708] Scheme J provides various general synthetic procedures forpreparing the novel intermediates of formula (X) wherein R₅ is H, Br,Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇.

[0709] In step a, the ketone functionality of the appropriateω-halo-halocumylketone compound of structure (10) is reduced to give thecorresponding ω-halo-halocumylalcohol compound of structure (60).

[0710] For example, reduction of the appropriate ω-halo-halocumylketonecompound of structure (10), using, for example, a suitable reducingagent such as sodium borohydride, potassium borohydride, sodiumcyanoborohydride, or tetramethylammonium borohydride is carried out inlower alcohol solvents, such as, methanol, ethanol, isopropyl alcohol orn-butanol at temperatures ranging from about 0° C. to the refluxtemperature of the solvent, and the reaction time varies from about ½hour to 8 hours. Other suitable reducing agents are, for example,lithium tri-tert-butylaluminohydride and diisobutylaluminum hydride.These reduction reactions are carried out in suitable solvents diethylether, tetrahydrofuran or dioxane at temperatures ranging from about 0°C. to the reflux temperature of the solvent, and the reaction timevaries from about ½ hour to 8 hours.

[0711] Catalytic reduction may also be employed in the preparation ofappropriate ω-halo-halocumylalcohol compound of structure (60) from anappropriate ω-halo-halocumylketone compound of structure (10), usinghydrogen gas in the presence of a suitable catalyst such as Raneynickel, palladium, platinum or rhodium catalysts in lower alcoholsolvents, such as, methanol, ethanol, isopropyl alcohol or n-butanol oracetic acid or their aqueous mixtures, or by the use of aluminumisopropoxide in isopropyl alcohol.

[0712] In addition, a chiral reduction of the appropriateω-halo-halocumylketone compound of structure (10), using, for example,(+)-B-chlorodiisopinocamphenylborane gives the corresponding(R)-ω-halo-halocumylalcohol compound of structure (60) and(−)-B-chlorodiisopinocamphenylborane gives the corresponding(S)-ω-halo-halocumylalcohol compound of structure (60). Other suitablechiral reducing agents are, (R) and (S)-oxazaborolidine/BH₃, potassium9-0-(1,2:5,6-di-O-isopropylidine-a-D-glucofuransoyl)-9-boratabicyclo[3.3.1]-nonane,(R) and (S)-B-3-pinanyl-9-borabicyclo[3.3.1]-nonane, NB-Enantride,Lithium (R)-(+) and (S)-(−)-2,2′-dihydroxy-1,1′-binaphthyl alkoxylaluminum hydride, (R)-(+) and(S)-(−)-2,2′-dihydroxy-6,6′-dimethylbiphenyl borane-amine complex,tris[[(1S,2S,5R)-2-isopropyl-5-methyl-cyclohex-1-yl]methyl]aluminum,[[(1R,3R)-2,2-dimethylbicyclo[2.2.1]hept-3-yl]methyl]beryllium chloride,(R)-BINAP-ruthenium complex/H₂ and6,6′-bis(diphenylphosphino)-3,3′-dimethoxy-2,2′,4,4′-tetramethyl-l,1′-biphenyl.

[0713] In step b, the ketone functionality of the appropriateω-halo-cyanocumylketone compound of structure (19) is reduced to givethe corresponding ω-halo-cyanocumylalcohol compound of structure (61) asdescribed previously in step a.

[0714] In step c, the ketone functionality of the appropriateω-halo-cyanocumylketone compound of structure (8) is reduced to give thecorresponding ω-halo-cyanocumylalcohol compound of structure (62) asdescribed previously in step a.

[0715] In step d, the α-halo functionality of the appropriateω-halo-halocumylalcohol compound of structure (60) is cyanated to givethe corresponding ω-halo-cyanocumylalcohol compound of structure (61) asdescribed previously in Scheme D, step a.

[0716] In step e, the appropriate ω-halo-cyanocumylalcohol compound ofstructure (62) is cyanated to give the correspondingω-halo-cyanocumylalcohol compound of structure (61) as describedpreviously in Scheme D, step b.

[0717] In step f, the appropriate appropriate ω-halo-cyanocumylalcoholcompound of structure (62) is halogenated to give the correspondingω-halo-halocumylalcohol compound of structure (60) as describedpreviously in Scheme B, step a.

[0718] In step g, the α-halo functionality of the appropriateω-halo-halocumylalcohol compound of structure (60) is converted to thecorresponding carboxy to give the′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) as described previously in Scheme H, step h.

[0719] In step h, the nitrile functionality of the appropriateω-halo-cyanocumylalcohol compound of structure (61) is converted to thecorresponding ester to give theω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid ester compound ofstructure (63) as described previously in Scheme H, step a.

[0720] In step i, the nitrile functionality of the appropriateω-halo-cyanocumylalcohol compound of structure (61) is converted to thecorresponding acid to give theω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) as described previously in Scheme H, step e.

[0721] In step j, the nitrile functionality of the appropriateω-halo-cyanocumylalcohol compound of structure (61).is converted to thecorresponding amide to give theω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid amide compound ofstructure (65) wherein R₆ and R₇ are each hydrogen as describedpreviously in Scheme H, step b.

[0722] In step k, the ketone functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound ofstructure (31) is reduced to give the correspondingω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid ester compound ofstructure (63) as described previously in step a.

[0723] In step 1, the ketone functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid compound of structure (46)is reduced to give the correspondingω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) as described previously in step a.

[0724] In step m, the ketone functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenylacetic acid amide compound ofstructure (40) is reduced to give the correspondingω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid amide compound ofstructure (65) as described previously in step a.

[0725] In step n, the carboxy ester functionality of the appropriateω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid ester compound ofstructure (63) is hydrolyzed to give the correspondingω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) as described previously in Scheme H, step c.

[0726] In step o, the carboxy functionality of the appropriateω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) may be esterified by techniques and procedures well known andappreciated by one of ordinary skill in the art to give thecorresponding ω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid estercompound of structure (63) as described previously in Scheme H, step d.

[0727] In step p, the carboxy functionality of the appropriateω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(65) may be amidated by techniques and procedures well known andappreciated by one of ordinary skill in the art to give thecorresponding ω-halo-α′-hydroxy-α,α-dimethylphenylacetic acid amidecompound of structure (57) as described previously in Scheme H, step g.

[0728] In step q, the amide functionality of the appropriateω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid amide compound ofstructure (65) is converted to the corresponding acid by acid hydrolysisas is known in the art to give theω′-halo-α′-hydroxy-α,α-dimethylphenylacetic acid compound of structure(64) as described previously in Scheme H, step f.

[0729] In addition, the novel intermediates of formula (X) wherein R₅ is—CH₂OD may be prepared as described in Scheme K. In Scheme K, allsubstituents are as previously defined unless otherwise indicated.

[0730] In Scheme K, the ketone functionality of the appropriateω′-halo-α′-keto-(2-methylpropanol)benzene compound of structure (60) isreduced to give the correspondingω′-halo-α′-hydroxy-(2-methylpropanol)benzene compound of structure (66)as described previously in Scheme J, step a.

[0731] The novel intermediates of formula (XI) wherein R₅ is hydrogen,CN, COOalkyl or CONR₆R₇ may be prepared as described in Scheme L. InScheme L, all substituents are as previously defined unless otherwiseindicated.

[0732] R₅′ is H, CN, COOalkyl or CONR₆R₇

[0733] Scheme L provides various general synthetic procedures forpreparing the novel intermediates of formula (XI) wherein R₅ ishydrogen, CN, COOalkyl or CONR₆R₇.

[0734] In step a, the ω′-halo functionality of the appropriateω′-halo-α′-keto-α,α-dimethylphenyl compound of structure (67) wherein R₅is hydrogen, CN, COOalkyl or CONR₆R₇ is alkylated with the appropriatepiperidine compound of structure (68) to give the correspondingω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R_(7.)

[0735] For example, the ω′-piperidine-α′-keto-α,α-dimethylphenylcompound of structure (69) wherein R₅ is hydrogen, CN, COOalkyl or CONR₆₇ may be prepared by reacting the appropriateω′-halo-α′-keto-α,α-dimethylphenyl compound of structure (67) wherein R₅is hydrogen, CN, COOalkyl or CONR₆R₇ with the appropriate piperidinecompound of structure (68) in a suitable solvent preferably in thepresent of a suitable non-nucleophilic base and optionally in thepresence of a catalytic amount of an iodide source, such as potassium orsodium iodide. The reaction time varies from about 4 to 120 hours andthe reaction temperature varies from about 70° C. to the refluxtemperature of the solvent. Suitable solvent for the alkylation reactioninclude alcohol solvents such as, methanol, ethanol, isopropyl alcohol,or n-butanol; ketone solvents, such as, cyclohexanone, methyl isobutylketone; hydrocarbon solvents, such as, benzene, toluene or xylene;halogenated hydrocarbons, such as, chlorobenzene or methylene chlorideor dimethylformamide. Suitable non-nucleophilic bases for the alkylationreaction include inorganic bases, for example, sodium bicarbonate,potassium carbonate, or potassium bicarbonate or organic bases, such as,a trialkylamine, for example, triethylamine or pyridine, or an excess ofan appropriate piperidine compound of structure (68) may be used.

[0736] For those piperidine compounds of structure (68), wherein R₁ ishydroxy, it is preferred that R₁ be unprotected for utilization in thealkyation reaction of step a, but those hydroxy functionalities presentin the piperidine compounds of structure (68), wherein R₁ is hydroxy maybe protected with a suitable protecting group. The selection andutilization of suitable protecting groups for the piperidine compoundsof structure (68), wherein R₁ is hydroxy is well known by one ofordinary skill in the art and is described in “Protective Groups inOrganic Syntheses”, Theodora W. Greene, Wiley (1981). For example,suitable protecting groups for those hydroxy functionalities presentinclude ethers such as tetrahydrothiopyranyl, tetrahydrothiofuranyl,2-(phenylselenyl)ethyl ether, o-nitrobenzyl ether, trimethylsilyl ether,isopropyldimethylsilyl ether, t-butyldimethylsilyl ether,t-butyldiphenylsilyl ether, tribenzylsilyl ether, triisopropylsilylether; and esters, such as acetate ester, isobutyrate ester, pivaloateester, adamantoate ester, benzoate ester, 2,4,6-trimethylbenzoate(mesitoate) ester, methyl carbonate p-nitrophenyl carbonate,p-nitrobenzyl carbonate, S-benzyl thiocarbonate and N-phenylcarbamate.

[0737] The piperidine compounds of structure (68) are readily availableto one of ordinary skill in the art and are described in U.S. Pat. No.4,254,129, Mar. 3, 1981, U.S. Pat. No. 4,254,130, Mar. 3, 1981, U.S.Pat. No. 4,285,958, Apr. 25, 1981 and U.S. Pat. No. 4,550,116, Oct. 29,1985. The piperidine compounds of structure (68) wherein R₁ and R₂ forma second bond between the carbon atoms bearing R₁ and R₂ may be preparedby dehydration of the corresponding compound wherein R₁ is hydroxy byprocedures generally known in the art, such as refluxing in stronglyacidic solution.

[0738] The piperidine compounds of structure (68) include thelimitations provided for previously for piperidine derivatives offormula (I) and (XI) in that when R₁ and R₂ are taken together to form asecond bond between the carbon atoms bearing R₁ and R₂ or where R₁represented hydroxy, m is an integer 0.

[0739] In step b, the ω′-halo functionality of the appropriateω-halo-α′-hydroxy-α,α-dimethylphenyl compound of structure (70) whereinR₅ is hydrogen, CN, COOalkyl or CONR₆R₇ is alkylated with theappropriate piperidine compound of structure (68) to give thecorresponding ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compound ofstructure (71) wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇ asdescribed previously in step a.

[0740] In step c, the ketone functionality of the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇ is reduced to give thecorresponding ω′-piperidine-′-hydroxy-α,α-dimethylphenyl compound ofstructure (71) wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇.

[0741] For example, reduction of the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇, using, for example, asuitable reducing agent such as sodium borohydride, potassiumborohydride, sodium cyanoborohydride, or tetramethylammonium borohydrideis carried out in lower alcohol solvents, such as, methanol, ethanol,isopropyl alcohol or n-butanol at temperatures ranging from about 0° C.to the reflux temperature of the solvent, and the reaction time variesfrom about ½ hour to 8 hours. Other suitable reducing agents are, forexample, lithium tri-tert-butylaluminohydride and diisobutylaluminumhydride. These reduction reactions are carried out in suitable solventsdiethyl ether, tetrahydrofuran or dioxane at temperatures ranging fromabout 0° C. to the reflux temperature of the solvent, and the reactiontime varies from about ½ hour to 8 hours.

[0742] Catalytic reduction may also be employed in the preparation ofappropriate ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compound ofstructure (71) wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇ from anappropriate ω′-piperidine-α′-keto-α,α-dimethylphenyl compound ofstructure (69) wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇, usinghydrogen gas in the presence of a suitable catalyst such as Raneynickel, palladium, platinum or rhodium catalysts in lower alcoholsolvents, such as, methanol, ethanol, isopropyl alcohol or n-butanol oracetic acid or their aqueous mixtures, or by the use of aluminumisopropoxide in isopropyl alcohol.

[0743] Reduction using sodium borohydride or potassium borohydride ispreferred over catalytic reduction for thoseω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇ and wherein R₁ and R₂taken together form a second bond between the carbon atoms bearing R₁and R₂-In addition, a chiral reduction of the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇, using, for example,(+)-B-chlorodiisopinocamphenylborane gives the corresponding(R)-ω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇ and(−)-B-chlorodiisopinocamphenylborane gives the corresponding(S)-ω′-piperidine-α′-keto-α,α-dimethylphenyl compound of structure (69)wherein R₅ is hydrogen, CN, COOalkyl or CONR₆R₇. Other suitable chiralreducing agents are, (R) and (S)-oxazaborolidine/BH₃, potassium9-O-(1,2:5,6-di-O-isopropylidine-α-D-glucofuransoyl)-9-boratabicyclo[3.3.1]-nonane,(R) and (S)-B-3-pinanyl-9-borabicyclo[3.3.1]-nonane, NB-Enantride,Lithium (R)-(+) and (S)-(−)-2,2′-dihydroxy-1,1′-binaphthyl alkoxylaluminum hydride, (R)-(+) and(S)-(−)-2,2′-dihydroxy-6,6′-dimethylbiphenyl borane-amine complex,tris[[(1S,2S,5R)-2-isopropyl-5-methyl-cyclohex-1-yl]methyl]aluminum,[[(1R,3R)-2,2-dimethylbicyclo[2.2.1-hept-3-yl]methyl]beryllium chloride,(R)-BINAP-ruthenium complex/H2 and6,6′-bis(diphenylphosphino)-3,3′-dimethoxy-2,2′,4,4′-tetramethyl-1,1′-biphenyl.

[0744] Starting materials for use in Scheme L are readily available toone of ordinary skill in the art.

[0745] The following examples present typical syntheses as described inScheme K. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 45 Step a:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid methyl ester

[0746] Mix methyl 4′-(4-chloro-1-oxobutyl)-α,α-dimethylbenzene acetate(0.335 mol), α,α-diphenyl-4-piperidinemethanol (101.8 g, 0.335 mol),potassium hydrogen carbonate (83.8 g, 0.838 mol), potassium iodide (1.00g, 0.006 mol), toluene (600 mL) and water (220 mL). Stir at reflux for72 hours, add toluene (200 mL) and deionized water (100 mL). Filterthrough filter aid while at 80° C. and separate the organic phase. Dry(MgSO₄), filter and purify by chromatography to give the title compound.

EXAMPLE 46 Step a:4-(4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl-α,α-dimethylbenzeneaceticacid ethyl ester

[0747] Method A: Remove the still head from the reaction flaskcontaining a solution of ethyl4′-(4-chloro-1-oxobutyl)-α,α-dimethylbenzene acetate and xylenesobtained from Example 11, Method G and reattach a reflux condenser. Atambient temperature, add azacyclonol free base which has beenrecrystallized from toluene (178.28 g, 0.660 mol) and stir at 175 RPMwhile heating by heating mantle. After the temperature of the reactionslurry reaches 137 (approximately 30 minutes), stir the reaction for 5.5hours, maintaining the temperature between 137-144 C. Remove the heatingmantle, add mixed xylenes (100 mL) and allow the reaction slurry to coolto 64 C. Increase the stirring rate to 300 RPM and add glacial aceticacid (15.17 g, 0.253 mol). Maintain the temperature at 64-69 C. for 1.9hours by heating with mantle, cool from 64-60 C. over a period of 15minutes; and from 60-50 C. over a period of 32 minutes; from 50-42 C.over a period of 33 minutes. Filter at 42 C. by suction through a 350 mLcoarse sintered glass filter funnel and wash the filtercake with mixedxylenes (200 mL) at ambient temperature. Allow the filtrate to stand atambient-temperature overnight then place in a 1 L flask. Add isopropanol(40 mL) and attached an overhead paddle stirrer. With stirring at 150RPM, slowly add 37% aqeuous concentrated HCl at ambient temperature,adding 2.00 g during the first 17 minutes, adding a total of 33.13 g ofHCl over 245 minutes. After the slurry has been digested, collect thesolids by suction filtration through a 350 mL coarse sintered glassfunnel and wash the filtercake with fresh xylenes (200 mL) and then withn-heptane (100 mL). Dry the filtercake under vacuum at 47 C. for 2.5days to give the title compound as an off-white solid (141.17 g, 81%).

[0748] Concentrate the filtrate by rotary evaporator to give a thickresidue of solids and syrup (23.78 g) Add acetone (68 g) and agitate byswirling until the syrup dissolves or releases as a solid. Collect thesolids by suction filtration through a medium sintered glass funnel,wash with fresh acetone (17 g) and dry under vacuum to give the titlecompound as a light tan solid (3.75 g).

[0749] Method B: Place the solution of ethyl4′-(4-chloro-1-oxobutyl)-α,α-dimethylbenzene acetate and xylenesobtained from Example 11, Method G in a 1 L, 3-neck round bottom flaskand add azacyclonol free base recrystallied from toluene (192.2 g, 0.719mol). Stir the resulting slurry by overhead stirrer and heat to 140 C.for 5.5 hours. Allow to cool to ambient temperature and add a mixture of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid ethyl ester hydrochloride (33.8 g, 0.0318 mol) and azacyclonolhydrochloride (0.0534 mol), slurried in mixed xylenes (100 mL). Reheatthe resulting slurry to 135 C. with stirring and then allow to coolslowly to ambient temperature.

[0750] Vacuum filter and wash the filtercake with xylenes. Dry thefiltercake under vacuum to give a solid (122.4 g). Concentrate thefiltrate by rotary evaporator to a weight to 486 g and add, by dropwiseaddition, 91 g (2.75 g, 0.0753 mol) of a solution of HCl gas (5.6 g) inabsolute 2 B ethanol (180 mL) at 70-80 C. over a 1.5 hour period. Coolslowly to 30 C. and filter by vacuum. Wash the filtercake with mixedxylenes and dry under vacuum at 50 C. to give the title compound as asolid (49.1 g).

[0751] To the filtrate from the second filtercake, add absolute 2 Bethanol (100 mL), heat to 50 C. and sparge gaseous HCl (about 5 g) intothe solution. Add additional mixed xylenes (170 mL) and absolute 2 Bethanol (100 mL) and heat to 70 C. Sparge in additional HCl gas untilthe total HCl added is 10 g (0.274 mol). Cool to 50 C. and stir for 2hours then cool to ambient temperature and stir overnight.

[0752] Distill a total of 240 mL of ethanol and xylenes from the slurryunder reduced pressure (80 mm, with pot temperature from 50 to 70 C. ).Cool to 30 C. over a 1 hour period and filter by vacuum. Wash thefiltercake with toluene and dry under vacuum at 50 C. to give the titlecompound as a solid (119.2 g).

[0753] Method C: Place ethyl4′-(4-chloro-1-oxobutyl)-α,α-dimethylbenzene acetate (15.00 g, 49.53mmol), azacyclonol free base (29.66 g, 49.53 mmol) and mixed xylenes (60mL) in a 250 mL 1-neck round bottom flask fitted with a magentic stirbar and reflux condenser. Heat the reaction mixture to reflux over aperiod of 15 minutes and then continue at reflux for 5.5 hours. Cool toambient temperature and then to ice/water bath temperature. Separate thesolids from the orange xylenes solution by suction filtration through acoarse sintered glass funnel, wash the filtercake with cold xylenes (25mL) and dry in a vacuum oven at 60 C. to give the title compound as anoff-white solid (16.21 g).

[0754] Method D: Place azacyclonol free base (35.00 g, 125.68 mmol),ethyl 4′-(4-chloro-1-oxobutyl)-α,α-dimethylbenzene acetate (17.30 g,57.13 mmol) and mixed xylenes (60 mL) into a 250 mL round bottom flask.Heat to reflux by mantel in 13 minutes and stir by megnetic bar and heatat reflux for 6.3 hours. Remove the heat from the reaction flask andcool by ice/water bath. Filter the cold reaction slurry by suctionthrough a coarse sintered glass funnel and wash the filtercake withfresh mixed xylenes (40 mL). Vacuum dry the filtercake at 40 C.overnight to give the title compound as a solid (17.87 g).

[0755] Add concentrated 37% HCl (2.18 g, 22.1 mmol) to the filtrate,stirred by magnetic bar. Stir overnight at ambient temperature, filterthrough suction through a coarse sintered glass funnel and wash thefiltercake with fresh mixed xylenes (35 mL) Vacuum dry the filtercake at50 C. to give the title compound as a solid (8.23 g).

[0756] Add concentrated 37% HCl (6.42 g, 65.2 mmol) to the filtratestirred by magnetic bar. Add mixed xylenes (70 mL) and filter though acoarse sintered glass funnel, at ambient temperature. Wash thefiltercake with fresh mixed xylenes (50 mL) and vacuum dry thefiltercake to give the title compound as a solid (27.25 g).

[0757] Purify by recrystallization as follows: Mix the title compound(15 g), absolute 2 B ethanol (45 mL) and n-heptane (90 mL) in a 500 mLround bottom flask with a magentic stir bar. Heat at reflux withstirring for 30 minutes, cool by ice/water bath and collect the solidsby suction filtration through a coarse sintered glass funnel. Wash thefiltercake with 3:1 n-heptane/ethanol (24 mL) and dry under vacuum at 55C. to give the title compound as a white solid.

EXAMPLE 47 Step c:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid

[0758] Add sodium borohydride (0.105 g, 2.77 mmol) to a solution ofsodium hydroxide (0.053 g, 1.33 mmol) in deionized water (2 mL) and add,by dropwise addition, to a solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (0.70 g, 1.31 mmol) in ethanol (30 mL). Stir at roomtemperature for 3.5 hours at pH 7-8. Evaporate the solvent in vacuo andstir the residue with methylene chloride (15 mL) and deionized water (15mL). Dry (MgSO₄), acidify to pH 3 with gaseous hydrogen chloride andevaporate the solvent. Add ether with stirring, filter the white solidand wash with additional ether. Dry to give the title compound.

EXAMPLE 48 Step c:(R)-4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic,ethyl ester

[0759] Dissolve (+)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8 mmol)in anhydrous tetrahydrofuran (5 mL). Add a solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl)-1-oxobutyl]-α,α-dimethylbenzeneacetic,ethyl ester (2 g, 3.54 mmol) in anhydrous tetrahydrofuran (5 mL). Stirat room temperature for 3 days and cool to 0° C. Add water (1 mL) and30% hydrogen peroxide (2 mL) and stir for 20 minutes. Add methylenechloride (30 mL) and wash with brine 4-30 mL), then aqueous sodiumhydrogen carbonate (30 mL), then brine (30 mL). Dry (MgSO₄), evaporatethe solvent in vacuo and purify by chromatography to give the titlecompound.

EXAMPLE 49 Step c:(S)-4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid, ethyl ester

[0760] Dissolve (−)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8 mmol)in anhydrous tetrahydrofuran (5 mL). Add a solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid, methyl ester (3.54 mmol) in anhydrous tetrahydrofuran (5 mL). Stirat room temperature for 3 days and cool to 0° C. Add water (1 mL) and30% hydrogen peroxide (2 mL) and stir for 20 minutes. Add methylenechloride (30 mL) and wash with brine (30 mL), then aqueous sodiumhydrogen carbonate (30 mL), then brine (30 mL). Dry (MgSO₄), evaporatethe solvent in vacuo and purify by chromatography to give the titlecompound.

EXAMPLE 50 Step a:N,N-Dimethyl-2-(4-{4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyryl}-phenyl)-isobutyramide

[0761] DissolveN,N-dimethyl-2-[4-(4-chlorobutyryl)-phenyl]-isobutyramide (l.00 g, 3.38mmol) in xylene (3 mL) and add α,α-diphenyl-4-piperidinemethanol (1.09g, 4.07 mmol) and potassium hydrogen carbonate (0.68 g, 6.76 mmol) inwater (2.5 mL). Heat at 100° C. for 20 hours, remove hot water bypipette, dilute with ethyl acetate (20 mL) and wash with water (20 mL).Cool the organic layer to room temperature, dry (MgSO₄), evaporate thesolvent in vacuo and purify by silica gel chromatography (9:1 ethylacetate/methanol) and recrystallize (ethyl acetate/hexane) to give thetitle compound (1.13 g, 63%) as a crystalline solid; mp 135-137° C.

EXAMPLE 51 Step c:N,N-Dimethyl-2-(4-(1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyryl)-phenyl)-isobutyramide

[0762] DissolveN,N-dimethyl-2-(4-(4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyryl)-phenyl)-isobutyramide(3.00 g, 5.69 mmol) in ethanol (30 mL), cool using an ice/water bath andadd sodium borohydride (0.87 g, 23.04 mmol) in tetrahydrofuran (10 mL).Remove the cold bath and stir at room temperature for 2.5 hours. Addwater (25 mL) and ethyl acetate (25 mL) and separate the layers. Extractthe aqueous layer with ethyl acetate (20 mL), dry (MgSO₄) and evaporatethe solvent in vacuo to give the title compound (3.06 g, 100%) as awhite foam; mp 166-169° C.

[0763] MS (CI, CH₄) m/e 529 (M⁺+1), 280, 183.

[0764] Anal. Calcd for C₃₄H₄₄N₂O₃.0.3H₂O: C., 77.24; H, 8.39; N, 5.30;Found: C, 76.99; H, 8.36; N. 5.17.

EXAMPLE 52 Step a:N-Methoxy-N-methyl-2-(4-{4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyryl}-phenyl)-isobutyramide

[0765] DissolveN-methoxy-N-methyl-2-[4-(4-chlorobutyryl)-phenyl]-isobutyramide (1.44 g,4.62 mmol) in 2:1 xylene/water (5 mL) and addα,α-diphenyl-4-piperidinemethanol (1.36 g, 5.07 mmol) and potassiumhydrogen carbonate (0.93 g, 9.24 mmol). Heat at 108° C. for 22 hours,remove hot water by pipette, cool to room temperature and stir for 2days. Evaporate the solvent in vacuo and purify by silica gelchromatography (10:1 ethyl acetate/methanol) and recrystallize (ethylacetate) to give the title compound (1.77 g, 71%) as a white crystallinesolid; mp 159-160.5° C.

[0766] MS (CI, CH₄) m/e 543 (M⁺+1), 293, 250, 183. Anal. Calcd forC₃₄H₄₂N₂O₄.0.3H₂O; C., 74.50; H, 7.83; N, 5.11; Found: C, 74.75; H,7.96; N. 5.15.

EXAMPLE 53 Step c:N-Methoxy-N-methyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butyryl}-phenyl)-isobutyramide

[0767] DissolveN-methoxy-N-methyl-2-(4-{4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyryl)-phenyl)-isobutyramide(8.83 g, 16.27 mmol) in 3.5:1 methanol/tetrahydrofuran (85 mL). Addsodium borohydride (0.62 g, 16.27 mmol) in 8 portions over 20 minutes atroom temperature. Stir at room temperature for 2 hours, evaporate thesolvent in vacuo, dissolve the residue in ethyl acetate (60 mL) and addwater (25m). Stir at room temperature for 10 minutes, separate thelayers and wash the organic layer with brine (2×25 mL). Combine theorganic layers, extract with ethyl acetate (35 mL), dry (Na₂SO₄),evaporate the solvent in vacuo and dry to give the title compound (8.89g, 100%) as a foam; mp 80-83° C.

[0768] MS (CI, CH₄) m/e 545 (M⁺+1), 280, 236, 183.

[0769] Anal. Calcd for C₃₄H₄₄N₂O₄.0.2H₂O: C., 74.47; H, 8.16; N, 5.12;Found: C, 74.08; H, 8.16; N. 4.93.

EXAMPLE 54 Step a:1-[4-(1,1-Dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-phenyl]-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butan-1-one

[0770] Dissolve4-chloro-1-[4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-phenyl]-butan-1-one(6.88 g, 21.38 mmol) in xylene (14 mL) and add a suspension ofα,α-diphenyl-4-piperidinemethanol hydrochloride (6.50 g, 23.51 mmol) andpotassium carbonate (6.14 g, 4.44 mmol) in water (30 mL). Heat at 100°C. for 24 hours, cool to room temperature, add methylene chloride (100mL) and separate the layers. Extract the aqueous layer with methylenechloride-(100 mL), wash with water (150 mL), dry (Na2SO₄), evaporate thesolvent in vacuo and purify by silica gel chromatography (4:1 ethylacetate/methanol) to give the title compound (8.20 g, 70%) as anoff-white solid.

[0771] Anal. Calcd for C₃₆H₄₄N₂O₃.2H₂O: C., 77.72; H, 8.04; N, 5.08;Found: C, 77.38; H, 7.91; N, 4.93.

EXAMPLE 55 Step c:2-(4-{1-Hydroxy-4-[4-hydroxydiphenylmethyl)-piperidin-1-yl]-butyl}-phenyl)-2-methyl-1-pyrrolidin-1-yl-propan-1-one

[0772] Dissolve1-[4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-phenyl]-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butan-1-one(0.55 g, 1.00 mmol) in methanol (10 mL) and add sodium borohydride (38mg, 1.00 mmol) at 10° C. Stir at room temperature for 2 hours, evaporatethe solvent in vacuo and dissolve the residue in methylene chloride (60mL). Add water (10 mL) and stir for 10 minutes. Separate the layers,wash with brine (5 mL), dry (Na₂SO₄) and evaporate the solvent in vacuoto give the title compound (0.53 g, 96%) as a white foam; mp 87-93° C.

EXAMPLE 56 Step a:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid, ethyl ester hydrochloride

[0773] Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid,ethyl ester (15.0 g, 49.53 mmol) and α,α-diphenyl-4-piperidinemethanol(29.66 g, 106.4 mmol) in xylene (60 mL). Reflux for 5.5 hours, cool inan ice bath, filter and wash with cold xylenes (25 mL). Filter thefiltrate though silica gel (20 g) and wash the gel with xylenes (40 mL).Add xylene (60 mL) and concentrated hydrochloric acid (6.45 g, 65.6mmol) with stirring. Add additional xylenes F40 mL) and stir for 2 hour.Filter, wash with xylene (50 mL), vacuum dry and slurry with a mixtureof ethanol (60 mL) and hexane (120 mL) at 70-72° C. for 30 minutes.Filter, wash with 3:1 v/v solution of n-heptane/ethanol (30 mL) and dryto give the title compound as a light white solid (19.7 g, 70%); mp206-208° C.

[0774]¹H NMR (300 MHz, CDCl₃) δ 7.90 (d, J=8.7 Hz, 2H), 7.47 (m, 4H),7.41 (d, J=8.7 Hz, 2H), 7.27 (m, 4H), 7.15 (m, 4H), 4.10 (q, J=7.1 Hz,2H), 2.93 (m, 4H), 2.37 (m, 3H), 2.2 (broad s, 1H), 1.92 (m, 4H), 1.59(s, 6H), 1.39 (m, 4H), 1.16 (t, J=7.1 Hz, 3H); 13 C. NMR (75 MHz, CDC₁₃)6 199.5, 176.1, 149.8, 146.0, 135.5, 128.2, 128.1, 126.4, 125.9, 125.7,79.4, 61.0, 57.8, 53.9, 46.7, 44.1, 36.3, 26.3, 26.2, 21.9, 14.0; IR(CDCl₃) 3514, 2945, 1726, 1682, 1446, 1254, 1147 1097 cm⁻¹;

[0775] Anal. Calcd for C₃₄H₄₁O₄N.HCl: C, 72.39; H, 7.50; N, 2.48; Found:C, 71.68; H, 7.52, N, 2.34.

EXAMPLE 57 Step a:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid, methyl ester hydrochloride

[0776] Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid,methyl ester (2.82 g, 10.0 mmol) and α,α-diphenyl-4-piperidinemethanol(5.58 g, 21.0 mmol) in toluene (20 mL). Reflux for 29 hours, cool in anice bath, filter, filter the filtrate though silica gel (5 g) and washthe gel with toluene (10 mL). Evaporate the solvent in vacuo anddissolve the residue in ethyl ether (100 mL). Add anhydrous hydrogenchloride and filter to give the title compound as-an off-white powder(4.2 g, 76%); mp 165-175° C. ¹H NMR (300 MHz, CDCl₃) δ 7.93 (d, J=8.3Hz, 2H), 7.47 (m, 4H), 7.42 (d, J=8.3 Hz, 2H), 7.30 (m, 4H), 7.18 (m,2H), 3.64 (s, 3H), 2.96 (m, 4H), 2.42 (m, 4H), 1.96 (m, 4H), 1.62 (s,6H), 1.41 (m, 4H); 13 C. NMR (75 MHz, CDC₁₃) δ 199.1, 176.3, 149.4,145.8, 135.5, 128.1, 128.0, 127.7, 126.3, 125.7, 1225.6, 79.4, 57.9,54.0, 52.4, 46.9, 44.1, 36.4, 26.4, 26.3, 22; MS (CI/NH₃) 514 (100(M+H)), 293 (4), 268 (7).

[0777] Anal. Calcd for C₃₃H₃₉O₄N.HCl: C., 72.05; H, 7.33; N, 2.55;Found: C, 71.85; H, 7.23, N, 2.33.

EXAMPLE 58 Step c:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid, methyl ester hydrochloride

[0778] Dissolve4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid, methyl ester hydrochloride (550 mg, 1.00 mmol) in methanol (5 mL)and add sodium borohydride (62.8 mg) in three batches. Stir for 1 hour,add 50% aqueous sodium hydroxide (800 mg) and heat to reflux withstirring. After 3 hours, cool to −10° C., add approximately 1.5 mL of 6NHCl over 10 minutes, filter the solid and wash with ice water (12 mL)such that the final filtrate is pH=5. Dry the resulting solid in vacuo(50-60° C., 10-1 mm) overnight to give the title compound (515 mg, 94%);mp 165-180° C.

[0779]¹H NMR (300 MHz, 5% MeOD₄ in CDCl₃) δ 7.50 (d, J=7.3 Hz, 4H), 7.30(m, 8H), 7.18 (t, J=7.0 Hz, 2H), 4.66 (t, J=5.3 Hz, 1H), 3.47 (m, 6H),2.97 (m, 2H), 2.69 (m, 3H), 1.6-2.2 (m, 6H), 1.55 (s, 6H); ¹³C NMR (75MHz, 5% MeOD₄ in CDCl₃) δ 179.1, 145.3, 143.8, 142.3, 128.2, 126.6,125.7, 125.5, 125.4, 78.4 (bis benzylic), 72.5 (benzylic), 57.4, 53.2,46.2, 24.2, 35.9, 26.6, 24.1, 20.8: MS (CI/NH₃) 502 (100⁻(M+H)), 280(5), 200 (10).

EXAMPLE 59 Step c:2-(4-(1-Hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl)-phenyl)-2-methyl-propanol

[0780] Dissolve2-(4-(1-oxo-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl)-phenyl)-2-methylpropanolin methanol (450 mL) and stir for 15 minutes at room temperature. Add,by dropwise addition, a solution of sodium borohydride (2.25 g, 0.06mol) in water (10 mL) over 15 minutes. Stir for another 30 minutes andcool in an ice-bath. Slowly add concentrated hydrochloric acid (4 mL)and water (8 mL) and stir for an additional 20 minutes. Evaporate thesolvent in vacuo and partition the residue between methylene chloride(150 mL) and water (70 mL). Separate the organic phase and extract theaqueous phase with methylene chloride (25 mL). Wash the combined organiclayers with water (2×50 mL), evaporate the solvent in vacuo andrecrystallize (acetone) to give the title compound as white needles(9.53 g, 79%).

[0781]¹H NMR (300 MHz, DMSO-d₆) δ 7.50 (4H, m), 7.23 (8H, m), 7.12 (2H,m), 5.34 (1H, s, br), 4.65 (1H, t), 4.45 (1H, s), 3.38 (2H, t), 2.60(2H, m), 2.44 (2H, m), 2.20 (2H, t), 1.62 (2H, t), 1.50 (6H, m), 1.98(6H, s); 13 C. NMR (DMSO-d₆) δ 147.2, 146.0, 143.4, 127.6, 125.6, 125.5,125.2, 78.4, 72.0, 70.9, 58.0, 53.6, 53.5, 43.6, 38.0, 30.5, 25.9, 25.5,23.1.

[0782] Alternatively, the novel intermediates of formula (XI) may beprepared as described in Scheme M. In Scheme M, all substituents are aspreviously defined unless otherwise indicated.

[0783] W═—C(═O)— or —CH(OH)—

[0784] Scheme M provides various alternative general syntheticprocedures for preparing the novel intermediates of formula (XI)

[0785] In step a, the appropriate ω′-piperidine-2-methylethylphenylcompound of structure (72) is cyanated to give the correspondingω′-piperidine-α,α-dimethylphenylacetonitrile compound of structure (73)as described previously in Scheme D, step b.

[0786] In step b, the appropriate ω′-piperidine-2-methylethylphenylcompound of structure (72) is halogenated to give the correspondingω′-piperidine-α,α-dimethylbenzyl halide compound of structure (74) asdescribed previously in Scheme B, step a.

[0787] In step c, the nitrile functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetonitrile compound of structure (73)is converted to the corresponding ester to give the′-piperidine-a,-dimethylphenylacetic acid ester compound of structure(75) as described previously in Scheme H, step a.

[0788] In step d, the halo functionality of the appropriate′-piperidine-α,α-dimethylbenzyl halide compound of structure (74) isconverted to the corresponding carboxy to give theω′-piperidine-α,α-dimethylphenylacetic acid compound of structure (76)as described previously in Scheme H, step h.

[0789] In step e, the nitrile functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetonitrile compound of structure (73)is converted to the corresponding carboxy to give theω′-piperidine-α,α-dimethylphenylacetic acid compound of structure (76)as described previously in Scheme H, step e.

[0790] In step f, the nitrile functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetonitrile compound of structure (73)is converted to the corresponding amide to give theω′-piperidine-α,α-dimethylphenylacetic acid amide compound of structure(77) wherein R₆ and R₇ are each hydrogen as described previously inScheme H, step b.

[0791] In step g, the carboxy ester functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetic acid ester compound of structure(75) is hydrolyzed to give the correspondingω′-piperidine-α,α-dimethylphenylacetic acid compound of structure (76)as described previously in Scheme H, step c.

[0792] In step h, the carboxy functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetic acid compound of structure (76)may be esterified by techniques and procedures well known andappreciated by one of ordinary skill in the art to give thecorresponding ω′-piperidine-α,α-dimethylphenylacetic acid ester compoundof structure (75) as described previously in Scheme H, step d.

[0793] In step i, the carboxy functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetic acid compound of structure (76)may be amidated by techniques and procedures well known and appreciatedby one of ordinary skill in the art to give the correspondingω′-piperidine-α,α-dimethylphenylacetic acid amide compound of structure(77) as described previously in Scheme H, step g.

[0794] In step j, the amide functionality of the appropriateω′-piperidine-α,α-dimethylphenylacetic acid amide compound of structure(77) is converted to the corresponding acid by acid hydrolysis as isknown in the art to give the ω′-piperidine-α,α-dimethylphenylacetic acidcompound of structure (76) as described previously in Scheme H, step f.

[0795] Starting materials for use in Scheme M are readily available toone of ordinary skill in the art.

[0796] The following examples present typical syntheses as described inScheme M. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; and “μM” refers to micromolar.

EXAMPLE 60 Step q:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid hydrochloride

[0797] Dissolve4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid methyl ester (0.131 mol) in methanol (2.5 L) and add 10% sodiumhydroxide (769 mL, 1.92 mol). Stir at reflux for 1.5 hours, cool to 68°C. and evaporate the solvent in vacuo to a residue. Add chloroform (1 L)and stir until the solids are dissolved. Separate the organic phase andextract the aqueous phase with chloroform (3×300 mL). Combine theorganic phases, dry (MgSO₄) and evaporate the solvent in vacuo to give aresidue. Treat the residue- with ethereal HCl, filter and dry to givethe title compound.

EXAMPLE 61 Step 1:4-(4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid

[0798] DissolveN-methoxy-N-methyl-2-(4-(1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butyryl}-phenyl)-isobutyramide(8.35 g, 15.33 mmol) in isopropanol (50 mL) and add potassium hydroxide(8.63 g, 153.7 mmol). Heat to reflux for 2 hours, add additionalpotassium hydroxide (4.35 g, 77.5 mmol) and heat at reflux for anadditional 16 hours. Cool to room temperature, treat with concentratedHCl by dropwise addition until pH=3. Dilute with water (100 mL), stirvigorously for 2 hours, add ethyl acetate (30 mL) and stir for 1 hour.Filter to give the title compound (7.15 g, 87%) as an off-white solid.

[0799] MS (CI, CH₄) m/e 502 (M⁺+1), 107.

[0800] Anal. Calcd for C₃₂H₃₉NO₄.HCl.2.6H₂O: C., 65.70; H, 7.61; N,2.39; Found: C, 65.25; H, 7.70; N, 2.36.

EXAMPLE 62 Step 1:4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid

[0801] DissolveN,N-dimethyl-2-(4-{1-hydroxy-4-(4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyry}-phenyl)-isobutyramide(15.33 mmol) in isopropanol (50 mL) and add potassium hydroxide (8.63 g,153.7 mmol). Heat to reflux for 2 hours, add additional potassiumhydroxide (4.35 g, 77.5 mmol) and heat at reflux for an additional 16hours. Cool to room temperature, treat with concentrated HCl by dropwiseaddition until pH=3. Dilute with water (100 mL), stir vigorously for 2hours, add ethyl acetate (30 mL) and stir for 1 hour. Filter to give thetitle compound (41%).

[0802] As one skilled in the art would appreciate, the compoundsdepicted in Schemes A through M which bear hydroxy or phenolicfunctionalities may be protected prior to use in the synthesis depictedin Schemes A through M using suitable protecting groups. For example,suitable protecting groups for the phenolic hydroxy include methylether, 2-methoxyethoxymethyl ether (MEM), cyclohexyl ether,o-nitrobenzyl ether, 9-anthryl ether, t-butyldimethylsilyl ether,acetate, benzoate, methyl carbamate, benzyl carbamate, aryl pivaloateand aryl methanesulfonate.

[0803] As one skilled in the art would appreciate, the compoundsdepicted in Schemes A through M which bear α-ketone functionalities maybe protected prior to use in the synthesis depicted in Schemes A throughM using suitable protecting groups. The selection and utilization ofsuitable protecting groups for ketone groups is well known by one ofordinary skill in the art and is described in “Protective Groups inOrganic Syntheses”, Theodora W. Greene, Wiley (1981). For example,suitable protecting groups for ketone functionalities include acyclicacetals and ketals such as dimethyl acetal, cyclic acetals and ketalssuch as 1,3-dioxanes and 1,3-dioxolanes, dithio acetals and ketals suchas 1,3-dithiane and 1,3-dithiolane, hemithio acetals and ketals,O-substituted cyanohydrins, substituted hydrozones, imines,oxazolidines, imidazolidines and thiazolidines.

[0804] As one skilled in the art would appreciate, the compoundsdepicted in Schemes A through M which bear protected hydroxy and/orketone functionalities may be reacting with appropriate deprotectingagents prior to use in any of the steps depicted in Schemes A through M.The selection and utilization of appropriate deprotecting reagents iswell known by one of ordinary skill in the art and is described in“Protective Groups in Organic Syntheses”, Theodora W. Greene, Wiley(1981). Examples of appropriate deprotecting reagents are mineral acids,strong organic acids, Lewis acids, aqueous mineral bases, catalytichydrogenation and the like.

[0805] For example, cleavage of β-methoxyethoxymethyl (MEM) protectinggroups on any of the compounds depicted in Schemes A through M whichbear protected hydroxy ketone functionalities, for example, can beachieved by using trifluoroacetic acid at room temperature or using 5 to8 equivalents of powdered anhydrous zinc bromide in methylene chlorideat about 25° C. by the general procedure of E. J. Corey et al.,Tetrahedron Letters, 11, 809-812 1976.

[0806] In addition, the individual (R) and (S) isomers of theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds of structure (71)can be prepared by techniques are procedures well known and appreciatedby one of ordinary skill in the art.

[0807] For example, the mixture of (R) and (S) isomers of theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds of structure (71)may be subjected to chiral chromatography to give the correspondingindividual (R)-ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds ofstructure (71) and (S)-ω′-piperidine-α′-hydroxy-α,α-dimethylphenylcompounds of structure (71).

[0808] In addition, the individual (R) and (S) isomers of theω-halo-α′-hydroxy-α,α-dimethylphenyl compound of structure (70) and theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds of structure (71)can be prepared by techniques and procedures well known and appreciatedby one of ordinary skill in the art and described in “Enanatiomers,Racemates, and Resolutions”, Jacques, Collet and Wilen, Wiley (1981).

[0809] One such method involves reacting the mixture of (R) and (S)isomers of the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds ofstructure (71) with appropriate chiral acids to give the correspondingmixture of diastereomeric acid addition salts. The individual(R)-ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl chiral acid additionsalt compounds of structure (71) and(S)-ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl chiral acid additionsalt compounds of structure (71) are obtained by recrystallization andthe individual ω′-piperidine-(R)-α′-hydroxy-α,α-dimethylphenyl compoundsof structure (71) and ω′-piperidine-(S)-α′-hydroxy-α,α-dimethylphenylcompounds of structure (71) are obtained by subjecting the individualω′-piperidine-(R)-α′-hydroxy-α,α-dimethylphenyl chiral acid additionsalt compounds of structure (71) andω′-piperidine-(S)-α′-hydroxy-α,α-dimethylphenyl chiral acid additionsalt compounds of structure (71) to base in order to free the piperidinenitrogen from the acid addition complex. Examples of suitable chiralacids are tartaric acid (+), (−), 0,0′-dibenzoyltartaric acid (+), (−),0,0′-di-p-toluyltartaric acid (+)(−) 2-Nitrotartranillic acid (+), (−),mandelic acid (+), (−), malic acid (+), (−), 2-phenoxypropionic acid(+), hydratropic acid (+), (−), N-acetylleucine (−), (+),N-(α-methylbenzyl)succinamide (+), (−), N-(α-methylbenzyl)phthalamicacid (+), (−), camphor-10-sulfonic acid (+), 3-bromocamphor-9-sulfonicacid (+), (−), camphor-3-sulfonic acid (+), quinic acid (+), (−),Di-0-isopropylidene-2-oxo-L-gulonic acid (−), Lasalocid (−),1,1′-binaphthyl-2,2′-phosphoric acid (+), (−), chloestenonesulfonicacid.

[0810] In addition, the individual (R) and (S) isomers of theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds of structure (71)can be prepared by reacting the mixture of (R) and (S) isomers of theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl compounds of structure (71)with appropriate organic chiral acids to give the corresponding mixtureof diastereomeric acid esters. The individualω′-piperidine-(R)-α′-ester-α,α-dimethylphenyl compounds of structure(71) and ω′-piperidine-(S)-α′-ester-α,α-dimethylphenyl compounds ofstructure (71) are obtained by recrystallization or chromatography andthe individual ω′-piperidine-(R)-α′-hydroxy-α,α-dimethylphenyl compoundsof structure (71) and ω′-piperidine-(S)-α′-hydroxy-α,α-dimethylphenylcompounds of structure (71) are obtained by subjecting the individualω′-piperidine-(R)-α′-ester-α,α-dimethylphenyl compounds of structure(71) and ω′-piperidine-(S)-α′-ester-α,α-dimethylphenyl compounds ofstructure (71) to hydrolysis conditions.

What is claimed is:
 1. A compound of the formula

wherein A is a hydrogen or hydroxy.
 2. A compound of the formula

wherein A is a hydrogen or hydroxy.
 3. A compound of the formula

wherein A is a hydrogen or hydroxy.
 4. A compound of the formula

wherein A is a hydrogen or hydroxy.
 5. A compound of the formula


6. A compound of the formula

wherein A is a hydrogen or hydroxy.
 7. A compound of the formula

wherein A is a hydrogen or hydroxy.
 8. A compound of the formula

wherein Hal is Cl, Br or I; n is an integer of from 1 to 5; A is ahydrogen or hydroxy; and R₅ is H, CH₂OD wherein D is hydrogen, acetateor benzoate, CHO, Br, Cl, I, CN, —COOH, —COOalkyl, —C(=NH)Oalkyl, or—CONR₆R₇, wherein the alkyl moiety has from 1 to 6 carbon atoms and isstraight or branched and R₆ and R₇ are each independently H, C₁-C₆alkyl,C₁-C₆alkoxy or R₆ and R₇ taken together with the nitrogen atom form apyrrolidine, piperidine or morpholine, with the proviso that R₆ and R₇cannot both be represented by C₁-C₆alkoxy.
 9. A compound according toclaim 8 wherein n is 3, Hal is Cl, R₅ is —COOCH₃ and A is hydrogen. 10.A compound of the formula

wherein Hal is Cl, Br or I; n is an integer of from 1 to 5; A is ahydrogen or hydroxy; and R₅ is H, OH, Br, Cl, I, CN, —COOH,—COOalkyl,—C(═NH)Oalkyl, or —CONR₆R₇ wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched and R₆ and R₇ are eachindependently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken togetherwith the nitrogen atom form a pyrrolidine, piperidine or morpholine,with the proviso that R₆ and R₇ cannot both be represented byC₁-C₆alkoxy.
 11. A compound of the formula

wherein Hal is Cl, Br or I; n is an integer of from 1 to 5; A is ahydrogen or hydroxy; and R₅ is H, OH, Br, Cl, I, CN, —COOH, —COOalkyl,—C(═NH)Oalkyl or —CONR₆R₇ wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched and R₆ and R₇ are eachindependently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken togetherwith the nitrogen atom form a pyrrolidine, piperidine or morpholine,with the proviso that R₆ and R₇ cannot both be represented byC₁-C₆alkoxy.
 12. A compound of the formula

wherein Hal is Cl, Br or I; n is an integer of from 1 to 5; A is ahydrogen or hydroxy; and R₅ is H, CH₂OD wherein D is hydrogen, acetateor benzoate, —CHO, Br, Cl, I, CN, —COOH, —COOalkyl, —C(═NH)Oalkyl or—CONR₆R₇ wherein the alkyl moiety has from 1 to 6 carbon atoms and isstraight or branched and R₆ and R₇ are each independently H, C₁-C₆alkyl,C₁-C₆alkoxy or R₆ and R₇ taken together with the nitrogen atom form apyrrolidine, piperidine or morpholine, with the proviso that R₆ and R₇cannot both be represented by C₁-C₆alkoxy; and individual opticalisomers thereof.
 13. A compound of the formula

wherein Hal is Cl, Br or I; n is an integer of from 1 to 5; and A is ahydrogen or hydroxy.
 14. A compound of the formula

wherein A is a hydrogen or hydroxy.
 15. A compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₅ is H, Br, Cl, I, CN or—CONR₆R₇ wherein R₆ and R₇ are each independently H, C₁-C₆alkyl,C₁-C₆alkoxy or R₆ and R₇ taken together with the nitrogen atom form apyrrolidine, piperidine or morpholine, with the proviso that R₆ and R₇cannot both be represented by C₁-C₆alkoxy; A is hydrogen or hydroxy; andpharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer
 0. 16. A process for preparing acompound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0 comprising using an intermediate compound ofthe formula

wherein A is a hydrogen or hydroxy; R₅ is H, —CH₂OD wherein D ishydrogen, acetate or benzoate, —CHO, Br, Cl, I, CN, —COOH, —COOalkyl or—CONR₆R₇ wherein the alkyl moiety has from 1 to 6 carbon atoms and isstraight or branched and R₆ and R₇ are each independently H, C₁-C₆alkyl,C₁-C₆alkoxy or R₆ and R₇ taken together with the nitrogen atom form apyrrolidine, piperidine or morpholine, with the proviso that R₆ and R₇cannot both be represented by C₁-C₆alkoxy.
 17. A process for preparing acompound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising using an intermediate compound ofthe formula

wherein A is a hydrogen or hydroxy; and R₅ is H, OH, Br, Cl, I, CN,—COOH, —COOalkyl or —CONR₆R₇ wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched and R₆ and R₇ are eachindependently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken togetherwith the nitrogen atom form a pyrrolidine, piperidine or morpholine,with the proviso that R₆ and R₇ cannot both be represented byC₁-C₆alkoxy.
 18. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0 comprising using an intermediate compound ofthe formula

wherein A is a hydrogen or hydroxy; and R₅ is H, OH, Br, Cl, I, CN,—COOH, —COOalkyl or —CONR₆R₇ wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched and R₆ and R₇ are eachindependently H, C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken togetherwith the nitrogen atom form a pyrrolidine, piperidine or morpholine,with the proviso that R₆ and R₇ cannot both be represented byC₁-C₆alkoxy.
 19. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0 comprising using an intermediate compound ofthe formula

wherein Hal is Cl, Br or I; n is an integer of from 1 to 5; A is ahydrogen or hydroxy; and R₅ is H, CH₂OD wherein D is hydrogen, acetateor benzoate, CHO, Br, Cl, I, CN, —COOH or —CONR₆R₇ wherein R₆ and R₇ areeach independently H—C₁-C₆alkyl, C₁-C₆alkoxy or R₆ and R₇ taken togetherwith the nitrogen atom form a pyrrolidine, piperidine or morpholine,with the proviso that R₆ and R₇ cannot both be represented byC₁-C₆alkoxy.
 20. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0 comprising using an intermediate compound ofthe formula

wherein Hal is Cl, Br or I; n is an integer of from 1 to 5; A is ahydrogen or hydroxy; and R₅ is H, OH, Br, Cl, I, CN, —COOH,—COOalkyl or—CONR₆R₇ wherein the alkyl moiety has from 1 to 6 carbonatoms and isstraight or branched and R₆ and R₇ are each independently H, C₁-C₆alkyl,C₁-C₆alkoxy or R₆ and R₇ taken together with the nitrogen atom form apyrrolidine, piperidine or morpholine, with the proviso that R₆ and R₇cannot both be represented by C₁-C₆alkoxy.
 21. A process for preparing acompound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0 comprising using an intermediate compound ofthe formula

wherein Hal is Cl, Br or I; n is an integer of from 1 to 5; A is ahydrogen or hydroxy; and R₅ is H, OH, Br, Cl, I, CN, —COOH, —COOalkyl or—CONR₆R₇ wherein the alkyl moiety has from 1 to 6 carbon atoms and isstraight or branched and R₆ and R₇ are each independently H, C₁-C₆alkyl,C₁-C₆alkoxy or R₆ and R₇ taken together with the nitrogen atom form apyrrolidine, piperidine or morpholine, with the proviso that R₆ and R₇cannot both be represented by C₁-C₆alkoxy.
 22. A process for preparing acompound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents-hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0 comprising using an intermediate compound ofthe formula

wherein Hal is Cl, Br or I; n is an integer of from 1 to 5; A is ahydrogen or hydroxy; and R₅ is H, CH₂OD wherein D is hydrogen, acetateor benzoate, CHO, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR₆R₇ whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched and R₆ and R₇ are each independently H, C₁-C₆alkyl, C₁-C₆alkoxyor R₆ and R₇ taken together with the nitrogen atom form a pyrrolidine,piperidine or morpholine, with the proviso that R₆ and R₇ cannot both berepresented by C₁-C₆alkoxy; and individual optical isomers thereof. 23.A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising using an intermediate compound ofthe formula

wherein Hal is Cl, Br or I; n is an integer of from 1 to 5; and A is ahydrogen or hydroxy.
 24. A process for preparing a compound of theformula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising using an intermediate compound ofthe formula

wherein A is a hydrogen or hydroxy.
 25. A process for preparing acompound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising using an intermediate compound ofthe formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₅ is H, Br, Cl, I, CN or—CONR₆R₇ wherein R₆ and R₇ are each independently H, C₁-C₆alkyl,C₁-C₆alkoxy or R₆ and R₇ taken together with the nitrogen atom form apyrrolidine, piperidine or morpholine, with the proviso that R₆ and R₇cannot both be represented by C₁-C₆alkoxy; A is hydrogen or hydroxy; andpharmaceutically acceptable salts and individual optical isomersthereof, with the proviso that where R₁ and R₂ are taken together toform a second bond between the carbon atoms bearing R₁ and R₂ or whereR₁ represented hydroxy, m is an integer
 0. 26. A process for preparing acompound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents-hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising the steps of: (a) reacting acumene compound of the formula

wherein A is as defined above with a ω-halo compound of the formula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is asdefined above, in the presence of a suitable Lewis acid to produce aω-halo cumylketone compound; (b) reacting the ω-halo cumylketonecompound with a suitable halogenating agent to give aω-halo-halocumylketone compound; (c) reacting the ω-halo-halocumylketonecompound compound with a suitable cyanating agent to give aω-halo-cyanocumylketone compound; (d) reacting theω-halo-cyanocumylketone compound with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable anhydrous acid togive a ω′-halo-α′-keto-α,α-dimethylphenylacetic acid imidate compound;(e) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid imidatecompound with water to give a ω′-halo-α′-keto-α,α-dimethylphenylaceticacid ester compound; (f) reacting theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound with apiperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)—; (g) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)— to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—; (h) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)— or theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—; and (i) optionally reactingthe ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula(I) wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is −5 C. H(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R₃ is—COOalkyl and W is —C(═O)—; and (j) optionally reacting the′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω-piperidine-α′-keto-a,-dimethylphenyl derivative of formula (I) whereinR₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-15 dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent, with the proviso that each of the hydroxy groupspresent in the compounds described in steps a-i are optionally protectedor unprotected.
 27. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising the steps of: (a) reacting aω-halo-halocumylketone compound with carbon dioxide underelectrochemical reduction conditions to give aω′-halo-α′-keto-α,α-dimethylphenylacetic compound; (b) reacting theω′-halo-α′-keto-α,α-dimethylphenylacetic compound compound with anappropriate straight or branched C₁-C₆ alcohol in the presence of asuitable anhydrous acid to give aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound; (c)reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound with a piperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce a ω′-piperidine-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOalkyl and W═—C(═O)—; (d)optionally hydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOalkyl and W is —C(═O)— toproduce a ω′-piperidine-α′-Keto-α,α-dimethylphenyl derivative of formula(I) wherein R₃ is COOH and W is —C(═O)—; (e) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)— or theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—; and (f) optionally reactingthe ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula(I) wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—or a′-piperidine-α′-keto-a,-dimethylphenyl derivative of formula (I) whereinR₃ is —COOalkyl and W is —C(═O)—; and (g) optionally reacting theω′-piperidine-α-keto-a,-dimethylphenyl derivative of formula (I) whereinR₃ is —COOH and W is —C(═O)—, the′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent, with the proviso that each of the hydroxy groupspresent in the compounds described in steps α-f are optionally protectedor unprotected.
 28. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents-hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integer3; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl wherein the alkylmoiety has from 1 to 6 carbon atoms and is straight or branched; each ofA is hydrogen or hydroxy; and pharmaceutically acceptable salts andindividual optical isomers thereof, with the proviso that where R₁ andR₂ are taken together to form a second bond between the carbon atomsbearing R₁ and R₂ or where R₁ represented hydroxy, m is an integer 0,comprising the steps of: (a) reacting a cumyl compound of the formula

wherein A is as defined above with an appropriate cyclopropyl compoundof the structure wherein B is halo or hydroxy, in the presence of asuitable Lewis acid to produce a cyclopropyl cumylketone compound; (b)reacting the cyclopropyl cumylketone compound with a suitablehalogenating agent to give a cyclopropyl halocumylketone compound; (c)reacting the cyclopropyl halocumylketone compound with carbon dioxideunder electrochemical reduction conditions to give acyclopropylketo-α,α-dimethylphenylacetic acid compound; (d) reacting thecyclopropylketo-α,α-dimethylphenylacetic with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable anhydrous acid togive a ω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound; (e)reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound with a piperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W═—C(═O)—; (f) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)— to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—; (g) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOalkyl and W is —C(═O)— or theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—; and (h) optionally reactingthe ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula(I) wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁-C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)—or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and (i) optionally reactingthe ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is -10 COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent, with the proviso that each of the hydroxy groupspresent in the compounds described in steps α-h are optionally protectedor unprotected.
 29. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising the steps of: (a) reacting a aα-dimethylphenylacetic acid amide compound of the formula

wherein A is as defined above and R₆ and R₇ are each independently H,C₁—C₆alkyl, C₁—C₆alkoxy or R₆ and R₇ taken together with the nitrogenatom for a pyrrolidine, piperidine or morpholine, with the proviso thatR₆ and R₇ cannot both be represented by C₁—C₆alkoxy with a ω-halocompound of the formula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is asdefined above, in the presence of a suitable Lewis acid to produce aω′-halo-α′-keto-α,α-dimethylphenylacetic acid amide compound; (b)reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid amidecompound with a piperidine compound of the formula

wherein R₁ and R₂ are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (XI)wherein R₅ is —CONR₆R₇ wherein R₆ and R₇ are as defined above; (c)optionally hydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (XI) wherein R₅ is —CONR₆R₇ wherein R₆ and R₇ areas defined above to produce a ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOH and W is —C(═O)—; (d)optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative of formula (I) wherein R₃ is COOH and W is —C(═O)— with asuitable reducing agent to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)—; and (e) optionally reacting theω′-piperidine-α′-hydroxy-30 α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)-with an appropriate straight orbranched C₁—C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and (f) optionally reactingthe ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-10 dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— with an appropriatedeprotecting reagent, with the proviso that each of the hydroxy groupspresent in the compounds described in steps a-e are optionally protectedor unprotected.
 30. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising the steps of: (a) reacting atoluene compound of the formula

wherein A is as defined above with a ω-halo compound of the formula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is asdefined above, in the presence of a suitable Lewis acid to producea.ω-halo-tolylketone compound; (b) reacting the ω-halo-tolylketonecompound with a suitable base to give a cyclopropyl-tolylketonecompound; (c) reacting the cyclopropyl-tolylketone compound with asuitable halogenating agent to give a cyclopropyl-halotolylketonecompound; (d) reacting the cyclopropyl-halotolylketone compound with asuitable cyanating agent to give a cyclopropyl cyanotolylketonecompound; (e) reacting the cyclopropyl cyanotolylketone compound with asuitable methylating agent to give a cyclopropyl cyanocumylketonecompound; (f) reacting the cyclopropyl cyanocumylketone compound with asuitable base to give a cyclopropylketo-α,α-dimethylphenylacetic acidamide; (g) reacting the cyclopropylketo-α,α-dimethylphenylacetic acidamide with an appropriate straight or branched C₁—C₆ alcohol in thepresence of a suitable anhydrous acid to give aω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound; (h)reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid estercompound with a piperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative; (i) optionallyhydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative toproduce a ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula(I) wherein R₃ is COOH and W is —C(═O)—; (j) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)—; and (k) optionallyreacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁—C₆ alcohol in the presence of a suitable acid to produce a′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (II)wherein R₃ is —COOalkyl and W is —C(═O)—; and (l) optionally reactingthe ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (II)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (II)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is—COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,with the proviso that each of the hydroxy groups present in thecompounds described in steps α-k are optionally protected orunprotected.
 31. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising the steps of: (a) reacting aphenylacetic acid ester compound of the formula

wherein A is as defined above with a ω-halo compound of the formula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is asdefined above, in the presence of a suitable Lewis acid to produce aω′-halo-α′-keto-phenylacetic acid ester compound; (b) reacting theω′-halo-α′-keto-phenylacetic acid ester compound with a suitablemethylating agent in the presence of a suitable base to give acyclopropylketo-α,α-dimethylphenylacetic acid ester; (c) purifying thecyclopropylketo-α,α-dimethylphenylacetic acid-ester by distillationand/or recrystallization; (d) reacting thecyclopropylketo-α,α-dimethylphenylacetic acid ester with an appropriatestraight or branched C₁—C₆ alcohol in the presence of a suitableanhydrous acid to give a ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound; (e) reacting theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound with apiperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; (f) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)— to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—; (g) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)— with a suitable reducing agent toproduce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)—; and (h) optionallyreacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative offormula (I) wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁—C₆ alcohol in the presence of a suitable acid to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and (i) optionally reactingthe ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is—COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,with the proviso that each of the hydroxy groups present in thecompounds described in steps α-h are optionally protected orunprotected.
 32. A process for preparing a compound of the formula

wherein W represents —C(═O)— or —CH(OH)—; R₁ represents hydrogen orhydroxy; R₂ represents hydrogen; or R₁ and R₂ taken together form asecond bond between the carbon atoms bearing R₁ and R₂; n is an integerof from 1 to 5; m is an integer 0 or 1; R₃ is —COOH or —COOalkyl whereinthe alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A is hydrogen or hydroxy; and pharmaceuticallyacceptable salts and individual optical isomers thereof, with theproviso that where R₁ and R₂ are taken together to form a second bondbetween the carbon atoms bearing R₁ and R₂ or where R₁ representedhydroxy, m is an integer 0, comprising the steps of: (a) reacting aphenylacetic acid ester compound of the formula

wherein A is as defined above with a suitable methylating agent to givea α,α-dimethylphenylacetic acid ester; (b) reacting theα,α-dimethylphenylacetic acid ester with a a ω-halo compound of theformula

wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is 3, inthe presence of a suitable Lewis acid to produce acyclopropylketo-α,α-dimethylphenykacetic acid ester; (c) purifying thecyclopropylketo-α,α-dimethylphenylacetic acid ester by distillationand/or recrystallization; (d) reacting thecyclopropylketo-α,α-dimethylphenylacetic acid ester with an appropriatestraight or branched C₁—C₆ alcohol in the presence of a suitableanhydrous acid to give a ω′-halo-α′-keto-α,α-dimethylphenylacetic acidester compound; (e) reacting theω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound with apiperidine compound of the formula

wherein R₁, R₂ and m are as defined above in the presence of a suitablenon-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; (f) optionally hydrolyzing theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)— to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is COOH and W is —C(═O)—; (g) optionally reacting theω-piperidine-α′-keto-a,-dimethylphenyl derivative of formula (I) whereinR₃ is COOH and W is —C(═O)— with a suitable reducing agent to produce aω′-piperidine-α′-hydroxy-a,-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)—; and (h) optionally reacting theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or the appropriateω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)— with an appropriate straight orbranched C₁—C₆ alcohol in the presence of a suitable acid produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —CH(OH)— or aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—; and (i) optionally reactingthe ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —C(═O)—, theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOalkyl and W is —C(═O)—, theω-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I)wherein R₃ is —COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R₃ is—COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,with the proviso that each of the hydroxy groups present in thecompounds described in steps a-h are optionally protected orunprotected.
 33. A process for preparing piperidine derivatives offormula

wherein W represents —C(═O)— or —CH(OH)—; R₃ is —COOH or —COOCH₃; andpharmaceutically acceptable salts and individual optical isomersthereof, comprising the steps of: (a) reacting phenylacetic acid methylester with a suitable methylating agent in the presence of a suitablebase to give α,α-dimethylphenylacetic acid methyl ester; (b) reactingα,α-dimethylphenylacetic acid methyl ester with a ω-halo compound of theformula

wherein B is halo or hydroxy and Hal represents Cl, Br or I in thepresence of a suitable Lewis acid to produce a mixture of meta and paraisomers of ω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl estercompounds of the formula

wherein Hal is defined above; (c) separating the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound bycrystallization; (d) reacting the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound witha piperidine compound of the formula

in the presence of a suitable non-nucleophilic base to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula

wherein W represents —C(═O); R₃ is —COOCH₃; and pharmaceuticallyacceptable salts and individual optical isomers thereof; (e) optionallyhydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivativewherein R₃ is COOCH₃ and W is —C(═O)— to produce aω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula

wherein W represents —C(═O)—; R₃ is —COOH; and pharmaceuticallyacceptable salts and individual optical isomers thereof; (f) optionallyreacting the ω′-piperidine-α-keto-a,-dimethylphenyl derivative whereinR₃ is COOCH₃ and W is —C(═O)— or theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R₃ is COOHand W is —C(═O)— with a suitable reducing agent to produce aω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R₃ is—COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R₃ isCOOCH3 and W is -10 C. H(OH)—; and (g) optionally reacting theω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R₃ is —COOHand W is —C(═O)—, the ω′-piperidine-α′-keto-α,α-dimethylphenylderivative wherein R₃ is —COOCH₃ and W is —C(═O)—, theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R₃ is—COOH and W is —CH(OH)— or theω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R₃ is—COOCH₃ and W is —CH(OH)— with an appropriate deprotecting reagent, withthe proviso that the hydroxy groups present in the compounds describedin steps α-f are optionally protected or unprotected.
 34. A processaccording to claim 33 wherein the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound isfurther separated from the meta isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound byrecrystallization of the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound. 35.A process according to claim 33 wherein additional para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound isrecovered from the mother liquors of the crystallization step (c),comprising the steps of: (a) reacting the mixture of meta and paraisomers of ω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl estercompounds with a suitable base such as sodium methoxide to give amixture of meta and para isomers of acyclopropyl-α,α-dimethylphenylacetic acid methyl ester of the formula

(b) enriching the para isomer of thecyclopropyl-α,α-dimethylphenylacetic acid methyl ester by removal of themeta isomer of the cyclopropyl-α,α-dimethylphenylacetic acid methylester by distillation; and (c) reacting the enriched para isomer of thecyclopropyl-α,α-dimethylphenylacetic acid methyl ester with a suitableanhydrous acid to give the enriched para isomer of theω-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound. 36.A process according to claim 35 wherein the enriched para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound isfurther separated from the meta isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound bycrystallization of the para isomer of theω-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound. 37.A process according to claim 36 wherein the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound isfurther separated from the meta isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound byrecrystallization of the para isomer of theω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound.